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2015 Antiemesis.Pdf

2015 Antiemesis.Pdf

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Antiemesis

Version 2.2015

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Version 2.2015, 09/22/15 © National Comprehensive Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. Printed by Alexandre Ferreira on 10/25/2015 6:12:07 AM. For personal use only. Not approved for distribution. Copyright © 2015 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 2.2015 Panel Members NCCN Guidelines Index Antiemesis Table of Contents Antiemesis Discussion

David S. Ettinger, MD/Chair † Steve Kirkegaard, PharmD Σ Eric Roeland, MD The Sidney Kimmel Comprehensive Huntsman Cancer Institute UC San Diego Moores Cancer Cancer Center at Johns Hopkins at the University of Utah Center

Michael J. Berger, PharmD/Vice Chair, BCOP Σ Dwight D. Kloth, PharmD, BCOP Σ Hope S. Rugo, MD † ‡ The Ohio State University Comprehensive Fox Chase Cancer Center UCSF Helen Diller Family Cancer Center - James Cancer Hospital Comprehensive Cancer Center and Solove Research Institute Ruth Lagman, MD £ Mayo Clinic Cancer Center Bridget Scullion, PharmD, BCOP Jonathan Aston, PharmD, BCOP, BCPS Σ Dana-Farber/Brigham and Women’s Vanderbilt-Ingram Cancer Center Dean Lim, MD † Cancer Center | Massachusetts City of Hope Comprehensive Cancer Center General Hospital Cancer Center Sally Barbour, PharmD, BCOP, CCP Σ Duke Cancer Institute Cynthia Ma, MD, PhD † John Timoney, PharmD, BCOP † Siteman Cancer Center at Barnes-Jewish Memorial Sloan Kettering Cancer Philip J. Bierman, MD † ‡ Hospital and Washington University School Center Fred & Pamela Buffet Cancer Center of Medicine Barbara Todaro, PharmD Σ Debra Brandt, DO Belinda Mandrell, PhD, RN † Roswell Park Cancer Institute Yale Cancer Center/Smilow Cancer Hospital St. Jude Children’s Research Hospital/ University of Tennessee Cancer Institute Susan G. Urba, MD † £ Dawn E. Dolan, PharmD, BCOP Σ University of Michigan Moffitt Cancer Center Laura Boehnke Michaud, PharmD, BCOP Σ Comprehensive Cancer Center The University of Texas Georgiana Ellis, MD † M.D. Anderson Cancer Center Fred Hutchinson Cancer Research Center/ Seattle Cancer Care Alliance Lisle M. Nabell, MD University of Alabama at Birmingham Eun Jeong Kim, PharmD, MS Σ Comprehensive Cancer Center Stanford Cancer Institute Kim Noonan, MS, RN, ANP, AOCN # Dana-Farber/Brigham and Women’s ‡ Hematology/hematology oncology Cancer Center | Massachusetts General Þ Internal medicine Hospital Cancer Center † Medical oncology # Nurse Σ NCCN Continue £ Supportive care including palliative, Miranda Hughes, PhD pain management, pastoral care, Dorothy A. Shead, MS and oncology social work NCCN Guidelines Panel Disclosures * Writing committee member

Version 2.2015, 09/22/15 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. Printed by Alexandre Ferreira on 10/25/2015 6:12:07 AM. For personal use only. Not approved for distribution. Copyright © 2015 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 2.2015 Table of Contents NCCN Guidelines Index Antiemesis Table of Contents Antiemesis Discussion

NCCN Antiemesis Panel Members Clinical Trials: NCCN believes that Guidelines Updates the best management for any cancer Principles of Emesis Control for the Cancer Patient (AE-1) patient is in a . Participation in clinical trials is especially encouraged. -INDUCED EMESIS: To find clinical trials online at NCCN High Emetic Risk Intravenous Chemotherapy - member institutions, click here: Acute and Delayed Emesis Prevention (AE-2) nccn.org/clinical_trials/physician.html. Moderate Emetic Risk Intravenous Chemotherapy - Emesis Prevention (AE-3) NCCN Categories of Evidence and Low and Minimal Emetic Risk Intravenous Chemotherapy - Emesis Prevention (AE-4) Consensus: All recommendations Oral Chemotherapy - Emesis Prevention (AE-5) are Category 2A unless otherwise specified. Breakthrough Treatment for Chemotherapy-Induced / (AE-6) Emetogenic Potential of Intravenous Antineoplastic Agents (AE-7) See NCCN Categories of Evidence and Consensus. Emetogenic Potential of Oral Antineoplastic Agents (AE-9) Principles of Managing Multiday Emetogenic Chemotherapy Regimens (AE-A) Principles for Managing Breakthrough Emesis (AE-B)

RADIATION-INDUCED EMESIS: Radiation-Induced Emesis Prevention/Treatment (AE-10)

ANTICIPATORY EMESIS: Anticipatory Emesis Prevention/Treatment (AE-11)

The NCCN Guidelines® are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no representations or warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. The NCCN Guidelines are copyrighted by National Comprehensive Cancer Network®. All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN. ©2015.

Version 2.2015, 09/22/15 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. Printed by Alexandre Ferreira on 10/25/2015 6:12:07 AM. For personal use only. Not approved for distribution. Copyright © 2015 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 2.2015 Updates NCCN Guidelines Index Antiemesis Table of Contents Antiemesis Discussion

Updates in Version 2.2015 of the NCCN Guidelines for Antiemesis from Version 1.2015 include: AE-2 AE-3 • High emetic risk intravenous chemotherapy - acute and delayed • Moderate emetic risk intravenous chemotherapy - emesis emesis prevention: prevention: Day 1 added: Day 1 added: ◊◊ 180 mg PO once (category 1). ◊◊Rolapitant 180 mg PO once (category 1). ◊◊If rolapitant given: 20 mg PO/IV once ◊◊Schwartzberg LS, et al. Lancet Oncol 2015;16:1071-1078. ◊◊Rapoport BL, et al. Lancet Oncol 2015;16:1079-1089. Day 2 and 3 added: Day 2, 3, 4 added: ◊◊Rolapitant used day 1: ± dexamethasone 8 mg PO/IV daily on ◊◊If rolapitant is given on day 1, dexamethasone 8 mg PO/IV twice daily days 2, 3 days 2, 3, 4

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. UPDATES Version 2.2015, 09/22/15 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. 1 OF 2 Printed by Alexandre Ferreira on 10/25/2015 6:12:07 AM. For personal use only. Not approved for distribution. Copyright © 2015 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines® Version 2.2015 Updates NCCN Guidelines Index Antiemesis Table of Contents Antiemesis Discussion Updates in Version 1.2015 of the NCCN Guidelines for Antiemesis from Version 2.2014 include: AE-2 AE-5 • The information on this page has been reformatted for clarity and • Oral chemotherapy - emesis prevention: consistency. High to moderate emetic risk, clarified 16-24 mg(total dose) • High emetic risk intravenous chemotherapy - acute and delayed emesis PO daily. prevention: Low to minimal emetic risk, clarified Removed “Preferred” from 0.25 mg IV day 1 ◊◊ 100 mg PO daily added “PRN” Day 1, added the following -containing regimen: ◊◊ 1-2 mg (total dose) PO added “PRN” ◊◊Netupitant 300 mg/palonosetron 0.5 mg PO once ◊◊Ondansetron 8-16 mg (total dose) PO daily added “PRN” ◊◊Dexamethasone 12 mg PO day 1 AE-8 ◊◊Hesketh P, Rossi G, Rizzi G et al. Efficacy and safety of NEPA, an • Emetogenic potential of Intravenous antineoplastic agents oral combination of netupitant and palonosetron, for prevention Added the following agents to low emetic risk: of chemotherapy-induced nausea and vomiting following highly ◊◊ emetogenic chemotherapy: a randomized dose ranging pivotal study. ◊◊Blinatumomab Ann Oncol 2014; 25: 1340–1346 Added the following agents to minimal emetic risk: Changed from every 4-6 h to every 6 h. (also applies to AE-3 ◊◊Nivolumab and AE-6) ◊◊Obinutuzumab Added a new footnote, “If neither nor are given ◊◊Pembrolizumab on day 1, then dexamethasone 20 mg PO/IV once on day 1, followed by 8 ◊◊Ramucirumab mg BID PO/IV on days 2, 3, 4. ◊◊Siltuximab AE-3 AE-9 • Moderate emetic risk intravenous chemotherapy - emesis prevention: • Emetogenic potential of oral antineoplastic agents Day 1, added the following netupitant-containing regimen: Added the following agents to moderate to high emetic risk: ◊◊Netupitant 300 mg/palonosetron 0.5 mg PO once ◊◊Ceritinib ◊◊Dexamethasone 12 mg PO day 1 ◊◊Lenvatinib ◊◊Aapro M, Rugo H, Rossi G, et al. A randomized phase III study ◊◊ evaluating the efficacy and safety of NEPA, a fixed-dose combination of ◊◊ netupitant and palonosetron, for prevention of chemotherapy-induced Added the following agents to minimal to low emetic risk: nausea and vomiting following moderately emetogenic chemotherapy. ◊◊Afatinib Ann Oncol 2014;25:1328-1333. ◊◊Ibrutinib Changed from days 2, 3, 4 to days 2, 3. ◊◊ Modified footnote “m”: As per high emetic risk prevention, aprepitant or ◊◊ fosaprepitant should be added (to dexamethasone and a 5-HT3 antagonist AE-11 regimen) for select patients with additional risk factors or who have failed • Anticipatory emesis prevention treatment, modified the following previous therapy with a + 5HT3 antagonist alone (See AE-2). recommendation Added a new footnote, “No further therapy required if palonosetron or “Consider therapy: granisetron patch given on day 1.” ◊◊For example, alprazolam 0.5-1 mg or lorazepam 0.5-2 mg PO TID beginning on the night before treatment and then repeated the next day 1-2 hours before chemotherapy begins AE-A • Principles of managing multiday emetogenic chemotherapy regimens: Included “transdermal” as an optional route of administration for antiemetic regimens. UPDATES

Version 2.2015, 09/22/15 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. 2 OF 2 Printed by Alexandre Ferreira on 10/25/2015 6:12:07 AM. For personal use only. Not approved for distribution. Copyright © 2015 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 2.2015 NCCN Guidelines Index Antiemesis Table of Contents Antiemesis Discussion

PRINCIPLES OF EMESIS CONTROL FOR THE CANCER PATIENT • Prevention of nausea/vomiting is the goal. The risk of nausea/vomiting for persons receiving chemotherapy of high and moderate emetic risk lasts for at least 3 days for high and 2 days for moderate after the last dose of chemotherapy. Patients need to be protected throughout the full period of risk. • Oral and intravenous 5-HT3 antagonists have equivalent efficacy when used at the appropriate doses. • Consider the toxicity of the specific antiemetic(s). • Choice of antiemetic(s) used should be based on the emetic risk of the therapy, prior experience with antiemetics, and patient factors. • There are other potential causes of emesis in cancer patients. These may include: Partial or complete Vestibular dysfunction Brain metastases Electrolyte imbalance: hypercalcemia, hyperglycemia, or hyponatremia Uremia Concomitant treatments, including opiates Gastroparesis: tumor or chemotherapy (eg, ) induced or other causes (eg, diabetes) Psychophysiologic: ◊◊Anxiety ◊◊Anticipatory nausea/vomiting • For use of antiemetics for nausea/vomiting that are not related to radiation and/or chemotherapy, see NCCN Guidelines for . • For multi-drug regimens, select antiemetic therapy based on the drug with the highest emetic risk. See Emetogenic Potential of Intravenous Antineoplastic Agents (AE-7). • Consider using an H2 blocker or proton pump inhibitor to prevent dyspepsia, which can mimic nausea. • Lifestyle measures may help to alleviate nausea/vomiting, such as eating small frequent meals, choosing healthful foods, controlling the amount of food consumed, and eating food at room temperature. A dietary consult may also be useful. See NCI’s “Eating Hints: Before, During, and After Cancer Treatment.” (http://www.cancer.gov/cancertopics/coping/eatinghints/page2#4)

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version 2.2015, 09/22/15 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. AE-1 Printed by Alexandre Ferreira on 10/25/2015 6:12:07 AM. For personal use only. Not approved for distribution. Copyright © 2015 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 2.2015 NCCN Guidelines Index Antiemesis Table of Contents Antiemesis Discussion HIGH EMETIC RISK INTRAVENOUS CHEMOTHERAPY - ACUTE AND DELAYED EMESIS PREVENTIONa,b DAY 1: Select option A, B, or C (order does not imply preference) DAYS 2, 3, 4: Start before chemotherapy:c d A: Aprepitant- or rolapitant-containing regimen: select one agent from A:k each of the following groups (category 1): If aprepitant PO given day 1, aprepitant 80 mg PO daily • Neurokinin-1 (NK1) antagonist: on days 2, 3 Aprepitant 125 mg PO once If fosaprepitant IV given on day 1, no further aprepitant Fosaprepitant 150 mg IV once is needed on days 2, 3 Rolapitant 180 mg PO oncee AND • (5-HT3) antagonist:f Dolasetron 100 mg PO once AND Granisetron 2 mg PO once, or 1 mg PO BID, or 0.01 mg/kg (max See 1 mg) IV once, or 3.1 mg/24 h transdermal patch applied 24-48 h Breakthrough prior to first dose of chemotherapy Treatment Ondansetron 16-24 mg PO once or 8-16 mg IV onceg  h If aprepitant PO given day 1, dexamethasone 8 mg PO/IV daily (AE-6) Palonosetron 0.25 mg IV once j AND days 2, 3, 4  • Steroid:i,j If fosaprepitant IV given on day 1, dexamethasone 8 mg PO/IV j If aprepitant/fosaprepitant given: Dexamethasone 12 mg PO/IV once on day 2, then 8 mg PO/IV BID days 3, 4 once If rolapitant is given on day 1, dexamethasone 8 mg PO/IV If rolapitant given: Dexamethasone 20 mg PO/IV once twice daily days 2, 3, 4 B: Netupitant-containing regimen:d,k B: Netupitant 300 mg/palonosetron 0.5 mg PO once Dexamethasone 8 mg PO/IV daily on days 2, 3, 4 Dexamethasone 12 mg PO/IV once C: Olanzapine-containing regimen:d,l C: Olanzapine 10 mg PO once Olanzapine 10 mg PO daily on days 2, 3, 4 Palonosetron 0.25 mg IV once Dexamethasone 20 mg IV once

aSee Emetogenic Potential of Intravenous Antineoplastic Agents (AE-7). bAntiemetic regimens should be chosen based on the drug with the highest emetic risk as well as patient- specific risk factors. cSee Principles of Managing Multiday Emetogenic Chemotherapy Regimens (AE-A). d With or without lorazepam 0.5-2 mg PO or IV or sublingual every 6 hours as needed days 1-4. iUse of is contraindicated with such as interleukin-2 (ie, IL-2, aldesleukin) and interferon. With or without H2 blocker or proton pump inhibitor See Principles of Emesis Control for the Cancer j Patient (AE-1) If neither aprepitant nor fosaprepitant are given on day 1, then dexamethasone 20 mg PO/IV once on e day 1, followed by 8 mg BID PO/IV on days 2, 3, 4. Rapoport BL, et al. Lancet Oncol 2015;16:1079-1089. k f Hesketh PJ, Rossi G, Rizzi G, et al. Ann Oncol 2014;25:1340-1346. Serotonin (5-HT3) antagonists may increase the risk of developing prolongation of the QT interval of l the electrocardiogram. See Discussion. Navari RM, Gray SE, Kerr AC. J Support Oncol 2011;9:188-195. m gThe FDA recommends a maximum of 16 mg for a single dose of IV ondansetron. Some NCCN Member Institutions use a 5-HT3 antagonist (unless palonosetron or granisetron patch hData with palonosetron are based on randomized studies in combination with steroids only. given on day 1) on days 2, 3, 4 in addition to steroid ± aprepitant. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version 2.2015, 09/22/15 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. AE-2 Printed by Alexandre Ferreira on 10/25/2015 6:12:07 AM. For personal use only. Not approved for distribution. Copyright © 2015 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 2.2015 NCCN Guidelines Index Antiemesis Table of Contents Antiemesis Discussion

MODERATE EMETIC RISK INTRAVENOUS CHEMOTHERAPY - ACUTE AND DELAYED EMESIS PREVENTIONa,b DAY 1: Select option A, B, or C (order does not imply preference) DAYS 2 and 3: Start before chemotherapy:c A: A: Serotonin (5-HT3) antagonist + steroid (category 1) ± NK-1 antagonistd • Serotonin (5-HT3) antagonist monotherapyq (Select one):f • Serotonin (5-HT3) antagonist (Select one):f Dolasetron 100 mg PO daily on days 2, 3 Dolasetron 100 mg PO once Granisetron 1-2 mg PO daily or 1 mg PO BID Granisetron 2 mg PO once, or 1 mg PO BID, or 0.01 mg/kg (max 1 or 0.01 mg/kg (maximum 1 mg) IV daily on days 2, 3 mg) IV once, or 3.1 mg/24 h transdermal patch applied 24-48 h prior Ondansetron 8 mg PO BID or 16 mg PO daily to first dose of chemotherapy or 8-16 mg IV daily on days 2, 3g Ondansetron 16-24 mg PO once or 8-16 mg IV onceg OR Palonosetron 0.25 mg IV onceh (preferred) i • Steroid monotherapy: See Breakthrough AND Dexamethasone 8 mg PO/IV daily on days 2, 3 Treatment (AE-6) • Steroid:i OR Dexamethasone 12 mg PO/IV once • NK1 antagonist ± steroid: i,j,n WITH/WITHOUT Aprepitant used day 1: Aprepitant 80 mg PO daily on • Neurokinin-1 (NK1) antagonist:n days 2, 3 ± dexamethasone 8 mg PO/IV daily on days 2, 3 Aprepitant 125 mg PO once Fosaprepitant used day 1: ± dexamethasone 8 mg PO or Fosaprepitant 150 mg IV once IV daily on days 2, 3 Rolapitant 180 mg PO once (category 1)o Rolapitant used day 1: ± dexamethasone 8 mg PO/IV daily on days 2, 3 B: B: Netupitant-containing regimen:d,p Netupitant 300 mg/palonosetron 0.5 mg PO once ± Dexamethasone 8 mg PO/IV daily on days 2, 3 Dexamethasone 12 mg PO/IV once C: C: Olanzapine-containing regimen:d,l Olanzapine 10 mg PO once Olanzapine 10 mg PO daily days 2, 3 Palonosetron 0.25 mg IV once Dexamethasone 20 mg IV once a See Emetogenic Potential of Intravenous Antineoplastic Agents (AE-7). j bAntiemetic regimens should be chosen based on the drug with the highest emetic risk as well as patient- If neither aprepitant nor fosaprepitant are given on day 1, dexamethasone 20 mg PO/IV once on day 1, specific risk factors. followed by 8 mg BID PO/IV on days 2, 3, 4. l cSee Principles of Managing Multiday Emetogenic Chemotherapy Regimens (AE-A). Navari RM, Gray SE, Kerr AC. J Support Oncol 2011;9:188-195. n dWith or without lorazepam 0.5-2 mg PO or IV or sublingual every 6 hours as needed days 1-4. As per high emetic risk prevention, aprepitant or fosaprepitant should be added (to dexamethasone With or without H2 blocker or proton pump inhibitor See Principles of Emesis Control for the Cancer and a 5-HT3 antagonist regimen) for select patients with additional risk factors or who have failed Patient (AE-1) previous therapy with a steroid + 5HT3 antagonist alone (See AE-2). fSerotonin (5-HT3) antagonists may increase the risk of developing prolongation of the QT interval of the oSchwartzberg LS, et al. Lancet Oncol 2015;16:1071-1078. electrocardiogram. See Discussion. pAapro M, Rugo H, Rossi G, et al. Ann Oncol 2014;25:1328-1333. gThe FDA recommends a maximum of 16 mg for a single dose of IV ondansetron. qNo further therapy required if palonsetron or granisetron patch given on day 1. hData with palonosetron are based on randomized studies in combination with steroids only. iUse of steroids is contraindicated with drugs such as interleukin-2 (ie, IL-2, aldesleukin) and interferon. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version 2.2015, 09/22/15 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. AE-3 Printed by Alexandre Ferreira on 10/25/2015 6:12:07 AM. For personal use only. Not approved for distribution. Copyright © 2015 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 2.2015 NCCN Guidelines Index Antiemesis Table of Contents Antiemesis Discussion

LOW AND MINIMAL EMETIC RISK INTRAVENOUS CHEMOTHERAPY - EMESIS PREVENTIONb,c,r

Start before chemotherapy (order does not imply preference) b,c,d Repeat daily for multiday doses of chemotherapy Dexamethasone 12 mg PO/IV dailyi or  10-40 mg PO/IV and then either every 4 or every 6 h PRNs or  10 mg PO/IV and then every 6 h PRN (maximum 40 mg/day)s Low or Serotonin (5-HT3) antagonistf (select one): Breakthrough Treatment ◊◊Dolasetron 100 mg PO daily for Chemotherapy-Induced ◊◊Granisetron 1-2 mg (total dose) PO daily Nausea/Vomiting (AE-6) ◊◊Ondansetron 8-16 mg PO daily

Minimal No routine prophylaxis

bAntiemetic regimens should be chosen based on the drug with the highest emetic risk as well as patient-specific risk factors. cSee Principles of Managing Multiday Emetogenic Chemotherapy Regimens (AE-A). dWith or without lorazepam 0.5-2 mg PO or IV or sublingual every 6 hours as needed days 1-4. With or without H2 blocker or proton pump inhibitor See Principles of Emesis Control for the Cancer Patient (AE-1) fSerotonin (5-HT3) antagonist may increase the risk of developing prolongation of the QT interval of the electrocardiogram. See Discussion. iUse of steroids is contraindicated with drugs such as interleukin-2 (ie, IL-2, aldesleukin) and interferon. rSee Emetogenic Potential of Intravenous Antineoplastic Agents (AE-8). sMonitor for dystonic reactions; use 25-50 mg PO or IV either every 4 or every 6 h for dystonic reactions. If allergic to diphenhydramine, use benztropine at 1-2 mg IV or IM x 1 dose, followed by oral dose of 1-2 mg daily or BID if needed to control the reaction. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version 2.2015, 09/22/15 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. AE-4 Printed by Alexandre Ferreira on 10/25/2015 6:12:07 AM. For personal use only. Not approved for distribution. Copyright © 2015 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 2.2015 NCCN Guidelines Index Antiemesis Table of Contents Antiemesis Discussion

ORAL CHEMOTHERAPY - EMESIS PREVENTIONb,c,t,u

Start before chemotherapy and continue daily (order does not imply preference)d • Serotonin (5-HT3) antagonist (Choose one):f High to Dolasetron 100 mg PO daily Breakthrough Treatment moderate Granisetron 1-2 mg (total dose) PO daily for Chemotherapy-Induced emetic risk Ondansetron 16-24 mg (total dose) PO daily Nausea/Vomiting (AE-6)

Start before chemotherapy and continue daily (order does not imply preference)d Metoclopramide 10-40 mg PO and then every 4 or every 6 h PRNs or Prochlorperazine 10 mg PO and then every 6 h PRN Low to s PRN Nausea/ (maximum 40 mg/day) minimal or recommended vomiting emetic risk  1-2 mg PO every 4 or every 6 h PRNs or Serotonin (5-HT3) antagonist (Choose one):f ◊◊Dolasetron 100 mg PO daily PRN ◊◊Granisetron 1-2 mg (total dose) PO daily PRN ◊◊Ondansetron 8-16 mg (total dose) PO daily PRN

sMonitor for dystonic reactions; use diphenhydramine 25-50 mg PO or IV either every 4 or every 6 h for dystonic reactions. If allergic to diphenhydramine, use bAntiemetic regimens should be chosen based on the drug with the highest emetic benztropine at 1-2 mg IV or IM x 1 dose, followed by oral dose of 1-2 mg daily or risk as well as patient-specific risk factors. BID if needed to control the reaction. cSee Principles of Managing Multiday Emetogenic Chemotherapy Regimens (AE-A). tSee Emetogenic Potential of Oral Antineoplastic Agents (AE-9). dWith or without lorazepam 0.5-2 mg PO or IV or sublingual every 6 hours as uThese antiemetic recommendations apply to oral chemotherapy only. When needed days 1-4. With or without H2 blocker or proton pump inhibitor combined with IV agents in a combination , the antiemetic See Principles of Emesis Control for the Cancer Patient (AE-1) recommendations for the agent with the highest level of emetogenicity should fSerotonin (5-HT3) antagonists may increase the risk of developing prolongation of be followed. If multiple oral agents are combined, emetic risk may increase and the QT interval of the electrocardiogram. See Discussion. require prophylaxis. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version 2.2015, 09/22/15 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. AE-5 Printed by Alexandre Ferreira on 10/25/2015 6:12:07 AM. For personal use only. Not approved for distribution. Copyright © 2015 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 2.2015 NCCN Guidelines Index Antiemesis Table of Contents Antiemesis Discussion

BREAKTHROUGH TREATMENT FOR CHEMOTHERAPY-INDUCED NAUSEA/VOMITING c,v RESPONSE TO SUBSEQUENT BREAKTHROUGH CYCLES The general principle of breakthrough treatment is to add one agent ANTIEMETIC TREATMENT from a different drug class to the current regimen. (order does not imply preference) • Atypical : w Olanzapine 10 mg PO daily for 3 days Continue Nausea and • : breakthrough vomiting Lorazepam 0.5-2 mg PO/SL/IV every 6 h , on a controlled • : schedule, not PRN  5-10 mg PO every 3-6 h Consider  1-2 mg PO BID changing • Other: antiemetic therapy Any Haloperidol 0.5-2 mg PO/IV every 4-6 hs to higher level nausea/ Metoclopramide 10-40 mg PO/IV every 4-6 hs primary treatment vomiting  transdermal patch 1 patch every 72 h for next cycle • : Prochlorperazine 25 mg supp pr every 12 h or 10 mg PO/IV every 6 hs Re-evaluate and  25 mg supp pr every 6 h or 12.5-25 mg PO/IV Nausea and/ consider dose (central line only) every 4-6 hs or vomiting adjustments and/or • Serotonin 5-HT3 antagonists:f uncontrolled switching to a Dolasetron 100 mg PO daily different therapy Granisetron 1-2 mg PO daily or 1 mg PO BID or 0.01 mg/kg (maximum 1 mg) IV daily Ondansetron 16 mg PO/IV daily • Steroid: Dexamethasone 12 mg PO/IV daily

cSee Principles of Managing Multiday Emetogenic Chemotherapy Regimens (AE-A). fSerotonin (5-HT3) antagonists may increase the risk of developing prolongation of the QT interval of the electrocardiogram. See Discussion. sMonitor for dystonic reactions; use diphenhydramine 25-50 mg PO or IV either every 4 or every 6 h for dystonic reactions. If allergic to diphenhydramine use benztropine at 1-2 mg IV or IM x 1 dose, followed by oral dose of 1-2 mg daily or BID if needed to control the reaction. vSee Principles of Managing Breakthrough Treatment (AE-B). wNavari RM, Nagy CK, Gray SE. The use of olanzapine versus metoclopramide for the treatment of breakthrough chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy. Support Care Cancer 2013;21:1655-1663. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version 2.2015, 09/22/15 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. AE-6 Printed by Alexandre Ferreira on 10/25/2015 6:12:07 AM. For personal use only. Not approved for distribution. Copyright © 2015 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 2.2015 NCCN Guidelines Index Antiemesis Table of Contents Antiemesis Discussion

EMETOGENIC POTENTIAL OF INTRAVENOUS ANTINEOPLASTIC AGENTSx

High emetic risk • AC combination defined as either • >1,500 mg/m2 • >90 mg/m2 (>90% frequency of emesis)y,z or epirubicin with • • ≥2 g/m2 per dose cyclophosphamide • Doxorubicin ≥60 mg/m2 • Mechlorethamine • >250 mg/m2 • Streptozocin •

2 aa 2 Moderate emetic risk • Aldesleukin >12-15 million IU/m • • Ifosfamide <2 g/m per dose 2 2 2 (30%-90% frequency of emesis)y,z • Amifostine >300 mg/m • Cyclophosphamide ≤1500 mg/m • Interferon alfa ≥10 million IU/m • • >200 mg/m2 • Irinotecanaa • • Dactinomycinaa • • • Daunorubicinaa • Methotrexateaa ≥250 mg/m2 • • Doxorubicinaa <60 mg/m2 • Oxaliplatin • Carboplatinaa • Epirubicinaa ≤90 mg/m2 • • Carmustineaa ≤250 mg/m2 •

Adapted with permission from: Hesketh PJ, et al. Proposal for classifying the acute emetogenicity of cancer chemotherapy. J Clin Oncol 1997;15:103-109 Grunberg SM, Warr D, Gralla RJ, et al. Evaluation of new antiemetic agents and definition of antineoplastic agent emetogenicity-state of the art. Support Care Cancer. 2010;19:S43-47.

Low Emetic Risk (See AE-8)

Minimal Emetic Risk (See AE-8)

Oral Chemotherapy (See AE-9)

xPotential drug interactions between antineoplastic agents / antiemetic therapies and various other drugs should always be considered. yProportion of patients who experience emesis in the absence of effective antiemetic prophylaxis. zContinuous infusion may make an agent less emetogenic. aaThese agents may be highly emetogenic in certain patients. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version 2.2015, 09/22/15 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. AE-7 Printed by Alexandre Ferreira on 10/25/2015 6:12:07 AM. For personal use only. Not approved for distribution. Copyright © 2015 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 2.2015 NCCN Guidelines Index Antiemesis Table of Contents Antiemesis Discussion

EMETOGENIC POTENTIAL OF INTRAVENOUS ANTINEOPLASTIC AGENTSx LEVEL AGENT Low emetic risk • Ado-trastuzumab emtansine • • 2 (10%-30% frequency of emesis)y • Amifostine ≤300 mg/m • • Omacetaxine • Aldesleukin ≤12 million IU/m2 • 5-FU • • Belinostat • • Paclitaxel-albumin • Blinatumomab • • • Brentuximab vedotin • Interferon alfa >5 <10 million • Pentostatin • Cabazitaxel international units/m2 • • • • • Cytarabine (low dose) 100-200 mg/m2 • >50 mg/m2 <250 mg/m2 • Thiotepa • Docetaxel • Mitomycin • • Doxorubicin (liposomal) • Ziv-aflibercept

Minimal emetic risk • Alemtuzumab • • Pertuzumab (<10% frequency of emesis)y • Asparaginase • Interferon alpha ≤5 million IU/m2 • Ramucirumab • Bevacizumab • Ipilimumab • Rituximab • • Methotrexate ≤50 mg/m2 • Siltuximab • • • Temsirolimus • Cetuximab • Nivolumab • Trastuzumab • • Obinutuzumab • (2-chlorodeoxyadenosine) • Ofatumumab • • Cytarabine <100 mg/m2 • Panitumumab • Vincristine • • • Vincristine (liposomal) • Denileukin diftitox • Peginterferon • • Dexrazoxane • Pembrolizumab Adapted with permission from: Hesketh PJ, et al. Proposal for classifying the acute emetogenicity of cancer chemotherapy. J Clin Oncol 1997;15:103-109 High Emetic Risk (See AE-7) Grunberg SM, Warr D, Gralla RJ, et al. Evaluation of new antiemetic agents and definition of antineoplastic agent emetogenicity-state of the art. Support Care Cancer. 2010;19:S43-47. Moderate Emetic Risk (See AE-7)

Oral Chemotherapy (See AE-9) xPotential drug interactions between antineoplastic agents / antiemetic therapies and various other drugs should always be considered. yProportion of patients who experience emesis in the absence of effective antiemetic prophylaxis. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version 2.2015, 09/22/15 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. AE-8 Printed by Alexandre Ferreira on 10/25/2015 6:12:07 AM. For personal use only. Not approved for distribution. Copyright © 2015 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 2.2015 NCCN Guidelines Index Antiemesis Table of Contents Antiemesis Discussion

EMETOGENIC POTENTIAL OF ORAL ANTINEOPLASTIC AGENTSx LEVEL AGENT Moderate to high • • Estramustine • Olaparib • Busulfan (≥4 mg/day) • Etoposide • Panobinostat • Ceritinib • Lenvatinib • • Crizotinib • (single day) • Temozolomide (>75 mg/m2/day) • Cyclophosphamide (≥100 mg/m2/day) • • Vismodegib Minimal to low • Afatinib • Gefitinib • Regorafenib • Axitinib • Hydroxyurea • Ruxolitinib • • Ibrutinib • Sorafenib • Bosutinib • Idelalisib • Sunitinib • Busulfan (<4 mg/day) • Imatinib • Temozolomide (≤75 mg/m2/day)bb • Cabozantinib • Lapatinib • • • Lenalidomide • Thioguanine • • Melphalan • Topotecan • Cyclophosphamide • • Trametinib (<100 mg/m2/day) • Methotrexate • Tretinoin • Dasatinib • Nilotinib • Vandetanib • Dabrafenib • Palbociclib • Vemurafenib • Erlotinib • Pazopanib • • Everolimus • Pomalidomide • Fludarabine • Ponatinib Adapted with permission from: Hesketh PJ, et al. Proposal for classifying the acute emetogenicity of cancer chemotherapy. J Clin Oncol 1997;15:103-109 Grunberg SM, Warr D, Gralla RJ, et al. Evaluation of new antiemetic agents and definition of antineoplastic agent emetogenicity-state of the art. Support Care Cancer. 2010;19:S43-47.

High Emetic Risk (See AE-7)

Moderate Emetic Risk (See AE-7)

Low Emetic Risk (See AE-8)

Minimal Emetic Risk (See AE-8)

xPotential drug interactions between antineoplastic agents / antiemetic therapies and various other drugs should always be considered. bbTemozolomide ≤75 mg/m2/day should be considered moderately emetogenic with concurrent radiotherapy. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version 2.2015, 09/22/15 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. AE-9 Printed by Alexandre Ferreira on 10/25/2015 6:12:07 AM. For personal use only. Not approved for distribution. Copyright © 2015 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 2.2015 NCCN Guidelines Index Antiemesis Table of Contents Antiemesis Discussion

RADIATION-INDUCED EMESIS PREVENTION/TREATMENT EMETOGENIC TYPE OF RADIATION THERAPY BREAKTHROUGH TREATMENT POTENTIAL

Start pretreatment for each day of RT treatment Radiation therapy (RT) - (order does not imply preference):f upper abdomen/localized • Granisetron 2 mg PO daily sites or • Ondansetron 8 mg PO BID • ± Dexamethasone 4 mg PO daily See Breakthrough Treatment (AE-6) Start pretreatment for each day of RT treatment (order does not imply preference):f Radiation-induced Total body irradiation • Granisetron 2 mg PO daily nausea/vomiting (TBI) or • Ondansetron 8 mg PO BID-TID • ± Dexamethasone 4 mg PO daily

Chemotherapy and RT See emesis prevention for chemotherapy-induced nausea/vomiting (including TBI) (High AE-2, Moderate AE-3, Low AE-4, and Oral AE-5)

fSerotonin (5-HT3) antagonists may increase the risk of developing prolongation of the QT interval of the electrocardiogram. See Discussion. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version 2.2015, 09/22/15 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. AE-10 Printed by Alexandre Ferreira on 10/25/2015 6:12:07 AM. For personal use only. Not approved for distribution. Copyright © 2015 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 2.2015 NCCN Guidelines Index Antiemesis Table of Contents Antiemesis Discussion

ANTICIPATORY EMESIS PREVENTION/TREATMENT

• Prevention is key: Use optimal antiemetic therapy during every cycle of treatment • Behavioral therapy: Relaxation/systematic desensitization Hypnosis/guided imagery Anticipatory Music therapy nausea/vomiting • /acupressure • Consider anxiolytic therapy: For example, alprazolam 0.5-1 mg or lorazepam 0.5-2 mg PO beginning on the night before treatment and then repeated the next day 1-2 hours before chemotherapy begins

See Primary and Breakthrough Treatments for Chemotherapy-Induced Nausea/Vomiting (Antiemesis TOC)

See Principles of Emesis Control for the Cancer Patient (AE-1)

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version 2.2015, 09/22/15 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. AE-11 Printed by Alexandre Ferreira on 10/25/2015 6:12:07 AM. For personal use only. Not approved for distribution. Copyright © 2015 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 2.2015 NCCN Guidelines Index Antiemesis Table of Contents Antiemesis Discussion

PRINCIPLES OF MANAGING MULTIDAY EMETOGENIC CHEMOTHERAPY REGIMENS1 Summary: • Patients receiving multiday chemotherapy are at risk for both acute and delayed nausea/vomiting based on the emetogenic potential of the individual chemotherapy agents administered on any given day and their sequence. It is therefore difficult to recommend a specific antiemetic regimen for each day, especially since acute and delayed emesis may overlap after the initial day of chemotherapy until the last day of chemotherapy. • After chemotherapy administration concludes, the period of risk for delayed emesis also depends on the specific regimen and the emetogenic potential of the last chemotherapy agent administered in the regimen. • Practical issues also need to be considered when designing the antiemetic regimen, taking into account the administration setting (eg, inpatient versus outpatient), preferred route of administration (IV, oral, or transdermal), duration of action of the serotonin antagonist and appropriate associated dosing intervals, tolerability of daily antiemetics (eg, ), and adherence/compliance issues.

General Principles: • Corticosteroids: Dexamethasone should be administered once daily (either orally or intravenously) for moderately or highly emetogenic chemotherapy and for 2 to 3 days after chemotherapy for regimens that are likely to cause significant delayed emesis. Dexamethasone dose may be modified or omitted when the chemotherapy regimen already includes a . Side effects associated with prolonged dexamethasone administration should be carefully considered. • Serotonin Antagonists: A serotonin antagonist should be administered prior to the first (and subsequent) doses of moderately or highly emetogenic chemotherapy. The frequency or need for repeated administration of the serotonin antagonist depends on the agent chosen and its mode of administration (IV, oral or transdermal). Palonosetron: ◊◊A single intravenous palonosetron dose of 0.25 mg may be sufficient prior to the start of a 3-day chemotherapy regimen instead of multiple daily doses of another oral or intravenous serotonin antagonist. ◊◊Repeat dosing of palonosetron 0.25 mg IV is likely to be safe, based on available evidence. ◊◊In terms of efficacy, the need for repeat dosing with palonosetron, either daily or less frequently, in the setting of multiday chemotherapy is not yet known. Continued on next page

1The panel acknowledges that evidence is lacking to support every clinical scenario. Decisions should be individualized for each chemotherapy regimen and each patient. An extensive knowledge of the available clinical data, pharmacology, pharmacodynamics, and of the antiemetics and the chemotherapy and experience with patients (regarding tolerability and efficacy) are all paramount to successfully implementing these guidelines into clinical practice.

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. AE-A Version 2.2015, 09/22/15 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. (1 OF 2) Printed by Alexandre Ferreira on 10/25/2015 6:12:07 AM. For personal use only. Not approved for distribution. Copyright © 2015 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 2.2015 NCCN Guidelines Index Antiemesis Table of Contents Antiemesis Discussion

PRINCIPLES OF MANAGING MULTIDAY EMETOGENIC CHEMOTHERAPY REGIMENS1 • NK1 Antagonists: Aprepitant or fosaprepitant may be used for multiday chemotherapy regimens likely to be highly emetogenic and associated with significant risk for delayed nausea and emesis. Category 1 evidence is available for single-day chemotherapy regimens only with aprepitant administered orally (as a 3-day regimen) in combination with a serotonin antagonist and corticosteroid (as noted on AE-2 and AE-3). Alternatively, for highly emetogenic regimens, fosaprepitant 150 mg IV with recommended dexamethasone dosing may be given on day 1 with no need for oral aprepitant on days 2 and 3. If the oral aprepitant regimen is chosen, phase II data exists to support administration of aprepitant on days 4 and 5 after multiday chemotherapy. It is not yet known if dosing aprepitant after day 3 improves control of nausea or emesis in this clinical setting. If the intravenous fosaprepitant regimen is chosen, pharmacokinetic data suggest that the single 150 mg intravenous dose provides antiemetic coverage for a similar period (up to 72 hours post chemotherapy). Studies investigating repeat dosing of intravenous fosaprepitant are not yet available. Data from a small phase III randomized study support the use of aprepitant (125 mg day 3, 80 mg days 4-7) with 5-HT3 antagonist (days 1-5) and dexamethasone (20 mg days 1, 2) in patients with germ line treated with a 5-day cisplatin-based chemotherapy. Reference: Albany C, Brames MJ, Fausel C, et al. Randomized, double-blind, placebo-controlled, phase III cross-over study evaluating the oral neurokinin-1 antagonist aprepitant in combination with a 5HT3 and dexamethasone in patients with germ cell tumors receiving 5-day cisplatin combination chemotherapy regimens: a hoosier oncology group study. J Clin Oncol 2012;30:3998-4003.

1The panel acknowledges that evidence is lacking to support every clinical scenario. Decisions should be individualized for each chemotherapy regimen and each patient. An extensive knowledge of the available clinical data, pharmacology, pharmacodynamics, and pharmacokinetics of the antiemetics and the chemotherapy and experience with patients (regarding tolerability and efficacy) are all paramount to successfully implementing these guidelines into clinical practice.

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. AE-A Version 2.2015, 09/22/15 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. (2 OF 2) Printed by Alexandre Ferreira on 10/25/2015 6:12:07 AM. For personal use only. Not approved for distribution. Copyright © 2015 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 2.2015 NCCN Guidelines Index Antiemesis Table of Contents Antiemesis Discussion

PRINCIPLES FOR MANAGING BREAKTHROUGH EMESIS • Breakthrough emesis presents a difficult situation, as correction of refractory ongoing nausea/vomiting is often challenging to reverse. It is generally far easier to prevent nausea/vomiting than it is to treat it. • The general principle of breakthrough treatment is to give an additional agent from a different drug class. No one drug class has been shown to be superior for the management of breakthrough emesis, and the choice of agent should be based on assessment of the current prevention strategies used. Some patients may require several agents utilizing differing mechanisms of action. • One should strongly consider routine, around-the-clock administration rather than PRN dosing. • The PO route is not likely to be feasible due to ongoing vomiting; therefore, rectal or IV therapy is often required. • Multiple concurrent agents, perhaps in alternating schedules or by alternating routes, may be necessary. antagonists (eg, metoclopramide, haloperidol), corticosteroids, and agents such as lorazepam may be required. • Ensure adequate hydration or fluid repletion, simultaneously checking and correcting any possible electrolyte abnormalities. • Prior to administering the next cycle of chemotherapy the patient should be reassessed, with attention given to various possible non- chemotherapy-related reasons for breakthrough emesis with the current cycle: Brain metastases Electrolyte abnormalities Tumor infiltration of the bowel or other gastrointestinal abnormality Other comorbidities • Prior to the next cycle of chemotherapy, reassess both the day 1 and post-chemotherapy antiemetic regimen, which did not protect the patient during the present cycle, and consider alternatives: (Suggestions are not in order of preference) Add aprepitant if not previously included. Add other concomitant antiemetics, (eg, dopamine antagonists such as metoclopramide or haloperidol). Possibly adjust dose(s), either intensity or frequency, of the 5-HT3 antagonist. Based on the patient’s experiences, the chemotherapy regimen in question may actually be more emetogenic than generally classified (eg, Hesketh method). Possibly switch to a different 5-HT3. Although not necessarily likely to be effective, anecdotal and limited investigational trial data suggest it may sometimes be efficacious. If the goal of chemotherapy is non-curative, consider other appropriate regimens, if any, that might be less emetogenic. It may be beneficial to add an anxiolytic agent in combination with the antiemetic agents. • Consider therapy if patient has dyspepsia (H2 blocker or proton pump inhibitor).

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version 2.2015, 09/22/15 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. AE-B Printed by Alexandre Ferreira on 10/25/2015 6:12:07 AM. For personal use only. Not approved for distribution. Copyright © 2015 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 2.2015 NCCN Guidelines Index Antiemesis Table of Contents Antiemesis Discussion

Discussion This discussion is being updated to correspond with the Serotonin (5-HT3) Receptor Antagonists ...... MS-4 newly updated algorithm. Last updated 04/18/14 Neurokinin-1–Receptor Antagonist ...... MS-7 NCCN Categories of Evidence and Consensus Drug Interactions ...... MS-9 Category 1: Based upon high-level evidence, there is uniform NCCN Other Non–5-HT3–Receptor Antagonist Antiemetics ...... MS-9 consensus that the intervention is appropriate. Treatment Issues ...... MS-10 Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate. Principles of Emesis Control ...... MS-11

Category 2B: Based upon lower-level evidence, there is NCCN Prevention of Acute and Delayed Emesis ...... MS-11 consensus that the intervention is appropriate. Prechemotherapy Emesis Prevention ...... MS-11 Category 3: Based upon any level of evidence, there is major NCCN Postchemotherapy/Delayed Emesis Prevention ...... MS-13 disagreement that the intervention is appropriate. Breakthrough Treatment...... MS-14 All recommendations are category 2A unless otherwise noted. Radiation-Induced Nausea and/or Vomiting ...... MS-15

Anticipatory Nausea and/or Vomiting ...... MS-15 Table of Contents Managing Multiday Emetogenic Chemotherapy Regimens ...... MS-16

Overview ...... MS-2 References ...... MS-19

Pathophysiology of Emesis ...... MS-2 Nausea ...... MS-2 Types of Nausea and/or Vomiting ...... MS-3

Chemotherapy-Induced Nausea and/or Vomiting ...... MS-3

Radiation-Induced Nausea and/or Vomiting ...... MS-3

Emetogenicity of Chemotherapy ...... MS-3

Types of Antiemetic Therapies ...... MS-4

Version 2.2015, 09/22/15 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. MS-1 Printed by Alexandre Ferreira on 10/25/2015 6:12:07 AM. For personal use only. Not approved for distribution. Copyright © 2015 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 2.2015 NCCN Guidelines Index Antiemesis Table of Contents Antiemesis Discussion

Overview Pathophysiology of Emesis Chemotherapy-induced (or radiation-therapy induced) vomiting (emesis) Vomiting results from stimulation of a multistep reflex pathway and nausea can significantly affect a patient’s quality of life, leading to controlled by the brain.5 Vomiting is triggered by afferent impulses to the poor compliance with further chemotherapy or radiation therapy vomiting center (located in the medulla) from the chemoreceptor trigger treatment. In addition, nausea and vomiting can result in metabolic zone, pharynx and gastrointestinal (GI) tract (via vagal afferent fibers), imbalances, degeneration of self-care and functional ability, nutrient and cerebral cortex. Vomiting occurs when efferent impulses are sent depletion, anorexia, decline of the patient’s performance status and from the vomiting center to the salivation center, abdominal muscles, mental status, wound dehiscence, esophageal tears, and withdrawal respiratory center, and cranial nerves.11 from potentially useful or curative anticancer treatment.1-4 The chemoreceptor trigger zone, vomiting center, and GI tract have The incidence and severity of nausea and/or vomiting in patients many neurotransmitter receptors. Activation of these receptors by receiving chemotherapy or radiation therapy (or both) are affected by chemotherapeutic agents or their metabolites may be responsible for numerous factors, including: (1) the specific chemotherapeutic agents chemotherapy-induced emesis. The principal neuroreceptors involved in used; (2) dosage of the agents; (3) schedule and route of administration the emetic response are the serotonin (5-hydroxytryptamine [5-HT3]) of the agents; (4) target of the radiation therapy (eg, whole body, upper and dopamine receptors.12,13 Other neuroreceptors involved in emesis abdomen); and (5) individual patient variability (eg, age, sex, prior include acetylcholine, corticosteroid, histamine, cannabinoid, opiate, chemotherapy, history of alcohol use).5,6 More than 90% of patients and neurokinin-1 (NK-1) receptors, which are located in the vomiting receiving highly emetogenic chemotherapy will have episodes of and vestibular centers of the brain.14 vomiting. However, only about 30% of these patients will vomit if they receive prophylactic (preventive) antiemetic regimens before treatment Antiemetic agents can block different neuronal pathways, exert their with highly emetogenic chemotherapy.5,7,8 Although vomiting can often effects at different points during the course of emesis, or behave be prevented or substantially decreased by using prophylactic synergistically with other antiemetic agents to potentiate an antiemetic antiemetic regimens, nausea is much harder to control.9,10 The NCCN effect. When used at a certain concentration, each antiemetic agent Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for predominantly blocks one receptor type. A final common pathway for Antiemesis is intended to provide an overview of the treatment emesis has yet to be identified. Therefore, no single agent can be principles for preventing chemotherapy- (or radiotherapy-) induced expected to provide complete protection from the various emetic phases vomiting and nausea, and recommendations for antiemetic prophylaxis of chemotherapy. according to the emetogenic potential of anti-tumor therapies. The Nausea NCCN Guidelines for Antiemesis is updated on a yearly basis by a multidisciplinary panel of experts. With use of effective antiemetic regimens, patients receiving emetogenic chemotherapy often experience more nausea than

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NCCN Guidelines Version 2.2015 NCCN Guidelines Index Antiemesis Table of Contents Antiemesis Discussion

vomiting.15-17 Vomiting and nausea are related; however, they may occur negative past experience with chemotherapy. The incidence of via different mechanisms. In general, younger patients are more likely to anticipatory nausea and/or vomiting ranges from 18% to 57%, and have nausea than older patients. Younger women receiving nausea is more common than vomiting.20,21 Younger patients may be chemotherapy for breast cancer are more prone to nausea than other more susceptible to anticipatory nausea and vomiting, because they populations.10 Delayed nausea is more common than acute nausea, is generally receive more aggressive chemotherapy and, overall, have often more severe, and tends to be resistant to treatment.17 poorer emesis control than older patients.22 Breakthrough emesis refers to vomiting that occurs despite prophylactic treatment and/or requires Types of Nausea and/or Vomiting “rescue” with antiemetic agents.23 Refractory emesis refers to emesis Chemotherapy-Induced Nausea and/or Vomiting that occurs during subsequent treatment cycles when antiemetic Nausea and/or vomiting induced by chemotherapy is commonly prophylaxis and/or rescue have failed in earlier cycles. classified as acute, delayed, anticipatory, breakthrough, or refractory. Radiation-Induced Nausea and/or Vomiting Acute-onset nausea and/or vomiting usually occurs within a few minutes to several hours after drug administration and commonly resolves within Patients receiving whole body or upper abdominal radiation therapy 23-25 the first 24 hours. The intensity of acute-onset emesis generally peaks have the greatest likelihood of developing nausea and/or vomiting. after 5 to 6 hours. The occurrence of acute emesis is influenced by the The GI tract (specifically, the small intestine) contains rapidly dividing patient's age and gender (females and younger patients [age < 50 cells that are particularly sensitive to radiation. In addition, the potential years] are more prone to emesis), environment in which chemotherapy for nausea and/or vomiting increases with larger daily fractional doses is administered, whether the patient has a history of chronic alcoholism of radiotherapy, larger total doses, and larger amounts of irradiated (which decreases the incidence of emesis) or , previous tissue. Total body irradiation, when given before marrow 23,26 episodes of nausea and vomiting, dosage of the emetogenic agent, and transplantation, commonly induces nausea and/or vomiting. efficacy of the antiemetic regimen.18,19 Emetogenicity of Chemotherapy Delayed-onset nausea and/or vomiting develop in patients more than The frequency of chemotherapy-induced emesis depends primarily on 24 hours after chemotherapy administration.18,19 It occurs commonly the emetogenic potential of the specific chemotherapeutic agents used. with the administration of cisplatin, , cyclophosphamide, Several classifications have been developed to define the and/or doxorubicin. For cisplatin, emesis reaches its maximal intensity emetogenicity of chemotherapy; however, none has been universally 48 to 72 hours after administration and can last 6 to 7 days. accepted.11,27-30

Anticipatory nausea and/or vomiting occur before patients receive their Hesketh and colleagues developed a classification of the acute next chemotherapy treatment. Because it is primarily considered a emetogenicity of anticancer chemotherapeutic agents and developed conditioned response, anticipatory emesis typically occurs after a an algorithm to define the emetogenicity of combination

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NCCN Guidelines Version 2.2015 NCCN Guidelines Index Antiemesis Table of Contents Antiemesis Discussion

chemotherapeutic regimens.7 The classification was recently updated Types of Antiemetic Therapies by Grunberg and colleagues; it divides chemotherapeutic agents into 4 In general, to provide maximal protection against chemotherapy- levels according to the percentage of patients not receiving antiemetic induced emesis, antiemetic therapy should be initiated before 9,31 prophylaxis who experience acute emesis. This classification, which chemotherapy. The antiemetic therapy should also be continued for the is updated each year by the NCCN Guidelines Panel with recently same length of time as the duration of the emetic activity of the introduced drugs, is used in these guidelines. Experts representing the chemotherapeutic agent being used. However, daily use of antiemetics panels of all of the published antiemetic treatment guidelines met to is not recommended for some therapeutic agents that are taken long prepare a single consensus document. Although this process is term (eg, imatinib, erlotinib). Antiemetic agents can be administered by 8,32 ongoing, the consensus guidelines have been published. The NCCN the oral, rectal, IV, intramuscular, or transdermal route. Oral and IV 5- Guidelines currently outline treatment using 4 categories of emetogenic HT3 antagonists have equivalent efficacy when used at the appropriate potential for intravenous (IV) agents, which correspond to the Grunberg doses.8,26 For patients at risk for CINV or unable to swallow or digest classification as follows: tablets because of emesis, IV antiemetics should be used. In selected patients who are unable to swallow, transdermal antiemetics may be of  High emetic risk—90% or more of patients experience acute emesis; value. Although studies may show drugs to be equally effective on a  Moderate emetic risk—30% to 90% of patients experience acute population basis, individual patients may respond differently. Therefore, emesis; some drug options may be based on a patient’s individual experience.  Low emetic risk—10% to 30% of patients experience acute emesis;  Minimal emetic risk—fewer than 10% of patients experience acute Serotonin (5-HT3) Receptor Antagonists emesis. The development of the 5-HT3–receptor antagonists (ie, dolasetron mesylate, granisetron, ondansetron, palonosetron) represents a In addition, the NCCN Guidelines attempt to define antiemetic regimens significant advance in antiemetic therapy.33-35 All of these agents have for particular chemotherapy drugs that cover the entire duration of time been shown to be effective in controlling the acute nausea and/or a patient is at risk for nausea and vomiting. Panel members were vomiting associated with cancer chemotherapy.35-49 concerned that some patients may not receive adequate prophylaxis for delayed emesis; therefore, the NCCN Guidelines incorporate a dosing Palonosetron is a 5-HT3 antagonist with an approximately 100-fold schedule that covers both acute and delayed emesis into a single higher binding affinity for the 5-HT3 receptor compared to the other algorithm. The NCCN Guidelines Panel members have also categorized serotonin antagonists (ie, ondansetron, granisetron, and dolasetron). It 9 the emetogenic potential of oral antineoplastic agents. has a half-life of approximately 40 hours, which is significantly longer than other commercially available 5-HT3 antagonists.35 Data suggest that palonosetron is associated with prolonged inhibition of the 5-HT3

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NCCN Guidelines Version 2.2015 NCCN Guidelines Index Antiemesis Table of Contents Antiemesis Discussion

receptor and thus differs from other 5-HT3 antagonists (eg, of patients who received concomitant dexamethasone (n=447), ondansetron, granisetron).50 palonosetron (0.25 mg IV) was similar to ondansetron (32 mg IV) in preventing acute emesis (CR rate 65% vs. 56%), but significantly more Several large, multicenter, double-blind, randomized phase III trials effective in preventing delayed emesis (CR rate 41% vs. 25%; have demonstrated the superiority of palonosetron compared with other P=0.021). In a more recent phase III randomized trial that compared 5-HT3 antagonists in preventing emesis associated with both moderate palonosetron (at a higher dose of 0.75 mg IV) with granisetron (40 and high emetic risk chemotherapy regimens, particularly for delayed mcg/kg IV), both in combination with dexamethasone, in patients 51-54 emesis. In these studies, the primary efficacy end point was treated with highly emetogenic chemotherapy (N=1114 evaluable), complete response (CR), defined as having no emesis and no rescue palonosetron showed similar activity to granisetron in preventing acute treatments. A study in patients receiving moderately emetogenic emesis (CR rate 75% vs. 73%), with superior activity in preventing chemotherapy (N=569 evaluable) showed that a single dose of delayed emesis (CR rate 57% vs. 44.5%; P<0.0001).54 A 3-drug palonosetron (0.25 mg IV) was comparable to a single dose of regimen using this higher dose of palonosetron (0.75 mg IV) in dolasetron (100 mg IV) for the prevention of acute chemotherapy- combination with dexamethasone and the neurokinin-1 receptor induced nausea and emesis (CR rate 63% vs. 53%, respectively); antagonist aprepitant was recently evaluated in a phase II study in moreover, IV palonosetron was superior to dolasetron in preventing patients with lung cancer undergoing highly emetogenic chemotherapy55 52 delayed emesis (CR rate 54% vs. 39%; P=0.004). Approximately 60% (see discussion section below, under “Neurokinin-1-Receptor of patients in the palonosetron arms and 70% in the dolasetron arm had Antagonist”). (Palonosetron (0.25 mg IV) is FDA approved as a single received in combination with cyclophosphamide; only 6% dose on day 1 for the prevention of acute and delayed nausea and 52 and 5% of patients, respectively, received concomitant corticosteroids. vomiting associated with moderately emetogenic chemotherapy and for In another study in patients receiving moderately emetogenic the prevention of acute nausea and vomiting associated with highly chemotherapy (N=563 evaluable), a single dose of palonosetron (0.25 emetogenic chemotherapy. It is the preferred 5-HT3 antagonist for the mg IV) was found to be superior to a single dose of ondansetron (32 mg prevention of acute and delayed emesis associated with high emetic IV) in preventing both acute (CR rate 81% vs. 69%; P<0.01) and risk IV chemotherapy and is also recommended (category 1) for emesis delayed emesis (CR rate 74% vs. 55%; P<0.01); no concomitant prevention when using moderate emetic risk IV chemotherapy (see 53 corticosteroids were given in this study The safety and side-effect Guidelines section on “High Emetic Risk Intravenous Chemotherapy - profiles of palonosetron were indistinguishable from the control 5-HT3 Acute and Delayed Emesis Prevention” and “Moderate Emetic Risk antagonists (ondansetron and dolasetron) using data submitted to the Intravenous Chemotherapy – Emesis Prevention; also see Discussion Food and Drug Administration (FDA). In a phase III randomized trial that section below for “Prevention of Acute and Delayed Emesis”). It should compared palonosetron with ondansetron in patients receiving highly be noted that the recommendation for palonosetron as the preferred 5- emetogenic chemotherapy (N=667), the majority (67%) had received HT3 antagonist for antiemetic prophylaxis in the setting of high emetic 51 dexamethasone on day 1 of antiemetic therapy. Among this subgroup risk chemotherapy is based upon data from randomized studies

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(discussed earlier) with the 2-drug combination of palonosetron and containing 34.3 mg of granisetron is applied approximately 24 to 48 dexamethasone. hours before the first dose of chemotherapy; the maximum duration of the patch is 7 days. A phase III randomized study compared the patch 55-58 Several recent studies have evaluated the efficacy of a 3-drug to oral granisetron in patients receiving either highly emetogenic or combination regimen with palonosetron, dexamethasone and the moderately emetogenic chemotherapy. The patch proved non-inferior to neurokinin-1 receptor antagonist aprepitant, in the management of repeat dosing of the oral antiemetic granisetron over 3 to 5 days.63,64 emesis in patients receiving moderately emetogenic and highly emetogenic (see discussion section below, under Many clinical trials directly comparing ondansetron, granisetron, “Neurokinin-1-Receptor Antagonist”). dolasetron mesylate, and palonosetron have been conducted. These trials have used various doses, routes, and schedules of Intravenous palonosetron is superior to other 5-HT3 antagonists for administration.51-54,65-78 A meta-analysis found no difference in efficacy 15,51-54 preventing delayed nausea. Repeat dosing of palonosetron in the between ondansetron, granisetron, and dolasetron mesylate.79 A recent days after chemotherapy (ie, days 2 or 3) is likely to be safe. However, meta-analysis of studies comparing ondansetron with granisetron has in the setting of multiple day (ie, multiday) chemotherapy, need for also confirmed the similar efficacy of these 5-HT3 antagonists in repeat dosing with palonosetron is not yet known (see Guidelines controlling acute and delayed nausea and vomiting, with similar safety section on “Managing Multiday Emetogenic Chemotherapy Regimens”). profiles between these agents.80 The most recent meta-analysis of randomized controlled trials comparing palonosetron with other Many of the 5-HT3 antagonists can be delivered orally or intravenously. available 5-HT3 antagonists demonstrated that palonosetron was Although oral palonosetron has been approved by the FDA for significantly more effective in preventing acute and delayed nausea and moderately emetic risk chemotherapy, it is not available in the United vomiting for both moderately and highly emetogenic chemotherapy States.59 Note that the IV dolasetron is no longer recommended for the agents.81 prevention of nausea and vomiting because IV dolasetron has been 60 associated with an increased risk for cardiac arrhythmias. Oral The addition of dexamethasone improves the efficacy of the antiemetic dolasetron is still recommended. Recently, the single IV dose of 32 mg regimen containing 5-HT3 antagonists; however, dexamethasone is ondansetron was removed from the prescription label based on FDA associated with side effects (such as insomnia). A recent randomized review of clinical data suggesting prolongation of the QT interval at this trial suggests that the dose of dexamethasone can be decreased to 8 61 dose. At this time, the FDA recommends a maximum single IV dose of mg on day 1 and also eliminated on days 2-3 when used with 16 mg with ondansetron; the dose recommendations for oral palonosetron for moderately emetic chemotherapy.82 administration of this agent remains unchanged.61 Ondansetron, granisetron, and dolasetron are effective in preventing In addition, the FDA has approved the use of a granisetron transdermal acute emesis but appear to be less effective for delayed emesis. A 62 system for chemotherapy-induced nausea and vomiting. The patch meta-analysis of randomized controlled trials found that adding a 5-HT3

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NCCN Guidelines Version 2.2015 NCCN Guidelines Index Antiemesis Table of Contents Antiemesis Discussion

antagonist to dexamethasone did not improve the antiemetic effect of dexamethasone) with or without the addition of aprepitant in patients dexamethasone for preventing delayed emesis.83 Another study found receiving emetogenic chemotherapy with high-dose cisplatin (N=521 that 5-HT3 antagonists (except palonosetron, which was not studied) evaluable), the addition of aprepitant was significantly more effective were not more effective than prochlorperazine for preventing delayed than the 2-drug regimen in controlling both acute (CR rate 89% vs. emesis.17 Intravenous palonosetron appears to be effective for 78%; P<0.001) and delayed emesis (CR rate 75% vs. 56%; P<0.001).89 preventing both delayed and acute emesis. Another similarly designed randomized phase III study (N=523 evaluable) also showed a significant benefit of adding aprepitant to 5-HT3–receptor antagonists have been associated with an increased ondansetron and dexamethasone compared with the 2-drug regimen risk for developing abnormal electrical activity of the heart (detectable alone for controlling both acute (CR rate 83% vs. 68%; P<0.001) and on ECG, including prolongation of electrocardiographic intervals such delayed emesis (CR rate 68% vs. 47%; P<0.001).90 A pooled analysis of 60,84-87 as PR or QT intervals). Although the ECG changes can be data combined from these two phase III trials found that the aprepitant reversible and asymptomatic, abnormal activity can also result in regimen was particularly beneficial in improving CR rates for patients potentially fatal cardiac arrhythmias (including Torsade de Pointes) in receiving concomitant emetogenic therapy with doxorubicin and/or some cases. Patients who may be particularly at risk for developing cyclophosphamide, along with high-dose cisplatin therapy.88 Torsade include those with congenital long QT syndrome or other underlying cardiac diseases, congestive heart failure, bradycardia, A meta-analysis (of 7 randomized controlled trials) in patients receiving those with electrolyte abnormalities (eg, hypokalemia or highly emetogenic chemotherapy found that NK-1 receptor antagonists hypomagnesemia), and those taking other medications that can lead to used alone or with standard therapy did not significantly increase QT prolongation.60,84 It is recommended that these patients undergo protection from acute emesis or nausea; however, for delayed emesis routine ECG monitoring during treatment with regimens that include 5- and nausea, NK-1 receptor antagonists was associated with HT3–receptor antagonists. significantly increased protection compared with control.91 In a recent meta-analysis (of 17 randomized controlled trials) that evaluated Neurokinin-1–Receptor Antagonist outcomes with standard antiemetic therapy with or without NK-1 Aprepitant selectively blocks the binding of substance P at the NK-1 receptor antagonists in patients receiving moderately or highly receptor in the central . Thus, aprepitant provides a emetogenic chemotherapy, the addition of NK-1 receptor antagonists different and complementary mechanism of action to other commercially was associated with significantly improved CR (no emetic episodes and available antiemetics. Aprepitant has been shown to augment the no rescue ) rate compared with standard therapy (72% vs. antiemetic activity of the 5-HT3–receptor antagonists and the 54%; P<0.001) during the overall time frame from 0 to 120 hours after corticosteroid dexamethasone to prevent both acute and delayed starting chemotherapy.92 The significant increase in CR rate associated cisplatin-induced emesis.88-90 In a randomized phase III trial comparing a with NK-1 receptor antagonists was observed for both the acute and standard antiemetic regimen (ondansetron 32 mg IV and oral delayed periods. Based on data from 3 trials that reported on infectious

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NCCN Guidelines Version 2.2015 NCCN Guidelines Index Antiemesis Table of Contents Antiemesis Discussion

complications, NK-1 receptor antagonists was associated with higher 1; 80 mg days 2, 3), and dexamethasone (20 mg IV day 1; 4 mg PO rates of severe compared with standard therapy (6% vs. 2%; days 2, 3) resulted in a CR rate (no emetic episodes and no rescue P<0.001); the risk of febrile neutropenia or other hematologic toxicities medication) of 70% during the overall study period (0–120 hours).58 In were not increased.92 addition, 93% of patients had no emesis and 60% had no nausea during the study period. was the most commonly reported A randomized phase III trial (N=866) showed that an aprepitant regimen adverse event (39%).58 In a recent phase II study that evaluated a was more effective than a standard regimen for preventing vomiting in higher dose of palonosetron (0.75 mg IV day 1) with aprepitant (125 mg patients receiving moderately emetogenic chemotherapy (non-cisplatin day 1; 80 mg days 2, 3), and dexamethasone (10 mg PO day 1; 8 mg based) during 120 hours after initiation of chemotherapy (CR rate 51% PO days 2–4) in patients with lung cancer undergoing highly vs. 43%, P=0.015); However, approximately 40% of patients (receiving emetogenic chemotherapy (N=63), the CR rate during the overall study 93 either regimen) still experienced significant nausea. The aprepitant period (0–120 hours) was 81%.55 The CR rates during the acute and regimen included aprepitant, ondansetron, and dexamethasone; the delayed phases were 97% and 81%, respectively. In addition, 54% of standard regimen included ondansetron and dexamethasone. patients had no nausea during the overall study period. Grade 1 or 2 constipation was the most commonly reported adverse event.55 A phase II study (N=58) found that combining palonosetron (0.25 mg IV day 1), aprepitant (125 mg day 1; 80 mg days 2, 3), and A randomized double-blind phase III study compared the effectiveness dexamethasone (12 mg day 1; 8 mg days 2, 3) was effective for of combining ondansetron (8 mg PO BID day 1), aprepitant (125 mg day preventing both acute and delayed emesis and nausea when using 1; 80 mg days 2, 3) and dexamethasone (12 mg day 1) versus standard various chemotherapeutic regimens (moderate to moderate-highly therapy with ondansetron (8 mg PO BID days 1-3) and dexamethasone emetogenic); 78% of patients had a CR (no emetic episodes and no (20 mg day 1) in patients receiving moderately emetogenic rescue medication) during the overall time frame, from 0 to 120 hours chemotherapy (N=585).94 Dexamethasone was only given on day 1 for 56 after initiation of emetogenic therapy. A phase II study in patients with both treatment groups. A significantly higher proportion of patients in the breast cancer (N=41) receiving moderately emetogenic chemotherapy 3-drug regimen with aprepitant had no vomiting compared with the also found that a single-day regimen of palonosetron (0.25 mg IV), standard group (76% vs. 62%; P<0.001) during the overall time frame aprepitant (285 mg oral), and dexamethasone (20 mg) was effective; from 0 to 120 hours after starting chemotherapy. In addition, the CR (no 76% and 66% of patients had a CR during the acute and delayed emetic episodes, no rescue medications) rate was significantly 57 phases, respectively. A 3-drug antiemetic regimen with palonosetron, increased in the aprepitant group (69% vs. 56%; P<0.001) during the dexamethasone and aprepitant has also been investigated in patients overall time period. The significant improvement in antiemetic activity undergoing treatment with highly emetogenic chemotherapies. A phase (with regards to no emesis as well as CR rate) in the aprepitant group II study in patients receiving highly emetogenic chemotherapy with was observed for both the acute and delayed phases. The 3-drug cisplatin-containing regimens (N=222) showed that the 3-drug combination of palonosetron (0.25 mg IV day 1), aprepitant (125 mg day

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NCCN Guidelines Version 2.2015 NCCN Guidelines Index Antiemesis Table of Contents Antiemesis Discussion

regimen was well tolerated, and the incidence of adverse events was Chemotherapeutic agents known to be metabolized by CYP3A4 include similar between treatment groups.94 , paclitaxel, etoposide, , ifosfamide, imatinib, vinorelbine, vinblastine, and vincristine. In clinical trials, aprepitant was Oral aprepitant is approved by the FDA for the prevention of nausea used concurrently with etoposide, vinorelbine, or paclitaxel; although and vomiting in patients receiving highly (eg, cisplatin-containing) and chemotherapy doses were not adjusted for potential drug interactions in 95 moderately emetogenic chemotherapy. The oral doses of aprepitant phase III trials, caution is urged when using any chemotherapeutic are 125 mg on day 1 (before chemotherapy) and then 80 mg on days 2 agent that is metabolized by CYP3A4. Aprepitant has been shown to 95,96 and 3 (after chemotherapy). An IV version of aprepitant interact with several non-chemotherapeutic drugs (including warfarin, (fosaprepitant dimeglumine), which can be given on day 1 only, is also dexamethasone, , oral contraceptives). Again, these approved by the FDA. IV fosaprepitant is given 30 minutes before interactions are more significant with orally administered forms of these 97 chemotherapy on day 1 only, per the package insert. If a higher dose drugs than with IV forms because of first-pass . of fosaprepitant is used (150 mg IV) on day 1, then it is not necessary to give oral aprepitant on days 2-3.98,99 Note that the dexamethasone Induction of warfarin metabolism by aprepitant may lead to clinically dosing is slightly different on days 3 and 4 (8 mg PO twice daily) when significant reductions in INR (international normalized ratio) values, using the higher dose of fosaprepitant (150 mg IV) per the package particularly for patients on therapeutic (as compared to prophylactic) insert.97 A single dose of 150 mg IV fosaprepitant was shown to be non- warfarin regimens. These changes, although brief in duration, may inferior to the standard regimen with 3-day oral aprepitant in a recent require increased patient monitoring.95 Aprepitant decreases the AUC randomized study.100 There are no studies showing efficacy or safety of for patients taking oral contraceptives; thus, other methods of birth chronic dosing with aprepitant. It is possible that the drug-drug control should be used during treatment with aprepitant and for 1 month interaction profile may change with chronic dosing. after the last dose of aprepitant.95 Additionally, certain drugs can affect the AUCs of aprepitant. Concomitant administration with CYP3A4 Drug Interactions inhibitors (eg, , itraconazole, and erythromycin) may lead Aprepitant is simultaneously a substrate, moderate inducer, and to increased aprepitant AUCs, whereas concomitant administration with moderate inhibitor of cytochrome P450 enzyme 3A4 (CYP3A4); CYP3A4 inducers (eg, carbamazepine, rifampin, and phenytoin) may 101 aprepitant also induces CYP2C9. Thus, aprepitant can alter the lead to decreased levels of aprepitant. metabolism of certain drugs and change their plasma concentrations (ie, AUCs [area under the curve]). These interactions are more Other Non–5-HT3–Receptor Antagonist Antiemetics significant with orally administered forms of these drugs than with IV Before the advent of the 5-HT3–receptor antagonists, the available forms because of first-pass metabolism. Patients should not take antiemetic agents included ,102 substituted aprepitant with pimozide, terfenadine, astemizole, or cisapride; these ,103,104 ,105 butyrophenones,106 combinations are contraindicated, because they may cause "serious or corticosteroids,107-109 ,110,111 and .112,113 Most life-threatening reactions" (see the aprepitant package insert )95

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NCCN Guidelines Version 2.2015 NCCN Guidelines Index Antiemesis Table of Contents Antiemesis Discussion

drugs used to prevent chemotherapy-induced emesis are classified as (77% vs. 73%) periods. The proportion of patients without nausea was dopamine antagonists, serotonin antagonists, and other antagonists. similar for the acute period (87% in each study arm) but the olanzapine Other agents such as gabapentin have also been evaluated as part of regimen was associated with a higher rate of nausea control during the antiemetic regimens. Combination antiemetic therapy is generally more delayed period (69% vs. 38%) compared with the aprepitant regimen.121 effective than single-agent therapy. However, olanzapine should be used with caution in elderly patients (see boxed warning/label indication regarding death in patients with Olanzapine (thiobenzodiazepine) was found to be effective for -related psychosis and additional warnings and precautions preventing acute and delayed emesis in a phase II trial in patients about type II diabetes and hyperglycemia).123,124 (N=30) who received cyclophosphamide, doxorubicin, and/or cisplatin;114 other studies have also showed the value of olanzapine for Gabapentin is an agent with and anti-seizure delayed and refractory emesis and nausea.115-118 Several studies have activities, and is indicated for the management of postherpetic neuralgia demonstrated the activity of olanzapine combined with a 5-HT3 receptor in adults and as adjunctive treatment for partial seizures associated with antagonist and dexamethasone in controlling emesis in patients epilepsy. A recent randomized, double-blind controlled pilot study receiving emetogenic chemotherapy regimens.119-122 A phase II study evaluated the activity and safety of adding gabapentin (versus placebo) evaluated the combination of olanzapine with palonosetron and to an antiemetic regimen (comprising ondansetron dexamethasone and dexamethasone in patients receiving highly emetogenic or moderately ranitidine) in patients receiving moderately or highly emetogenic emetogenic chemotherapy regimens (N=40).119 Among patients chemotherapy (N=80).125 The CR rate (complete protection from undergoing highly emetogenic chemotherapy (n=8), the CR rate was vomiting or nausea) during the course of the study (days 1 to 5) was 75% during the overall study period (0–120 hours); the CR rates for the higher in the gabapentin arm compared with the placebo arm (62.5% acute phase (0–24 hours) and delayed phase (24–120 hours) were vs. 40%). In addition, among the patients who had a CR during the 100% and 75%, respectively. The corresponding CR rates among the acute period, the CR rate for the delayed period (24-120 hours post- patients receiving moderately emetogenic chemotherapy (n=32) were chemotherapy) was also improved with gabapentin (89% vs. 61%).125 72%, 97%, and 75%, respectively.119 More recently, a randomized phase III study evaluated the effectiveness of olanzapine (10 mg PO Treatment Issues day 1–4) versus aprepitant (125 mg PO day 1, 80 mg PO days 2, 3) for As new data on the use of antiemetics in patients receiving preventing acute and delayed emesis in patients (N=251) receiving chemotherapy become available, clinicians should consider these data highly emetogenic chemotherapy (cisplatin, cyclophosphamide and when caring for such patients, even if the information has not been doxorubicin); both treatment arms included the 5-HT3–receptor included in the guidelines. In contrast to other NCCN Guidelines in antagonist palonosetron (0.25 mg IV day 1) and dexamethasone.121 The which most of the recommendations are category 2A, many of the CR (no emesis, no rescue) rate was similar between the olanzapine and recommendations for antiemetic management are classified as category aprepitant regimens, both during the acute (97% vs. 87%) and delayed

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NCCN Guidelines Version 2.2015 NCCN Guidelines Index Antiemesis Table of Contents Antiemesis Discussion

1, reflecting the large number of randomized controlled trials that have Prechemotherapy Emesis Prevention focused on antiemetic management. The NCCN Guidelines specify different prophylactic antiemetic regimens for cancer patients receiving chemotherapy of different Principles of Emesis Control emetogenic potential (ie, high, moderate, low, and minimal). These principles are described in the algorithm and are summarized Prophylactic antiemetics should be administered before chemotherapy. here (see Guidelines section on “Principles of Emesis Control for the The recommendations for prophylactic antiemetic treatment include Cancer Patient”). The goal of emesis control is to prevent nausea drug dosages. The guidelines reflect accumulating experience with the and/or vomiting. Antiemetic regimens should be chosen based on the 5-HT3 antagonists, demonstrating their effectiveness in a range of drug with the highest emetic risk in the chemotherapy regimen, previous doses. Unless indicated, the order of listed antiemetics in the NCCN experience with antiemetics, and patient-specific risk factors.9 Patients Guidelines does not reflect preference. need to be protected throughout the entire period of risk, which lasts for at least 3 days for high emetic risk and 2 days for moderate emetic risk Highly emetogenic IV drugs in the NCCN Guidelines include carmustine 2 2 agents after the last dose of chemotherapy. (>250 mg/m ), cisplatin (any dose), cyclophosphamide (>1500 mg/m ), dacarbazine, doxorubicin (≥ 60 mg/m2), epirubicin (> 90 mg/m2), In addition to using antiemetic regimens, patients can adjust their eating ifosfamide (≥ 2 g/m2 per dose), mechlorethamine, streptozocin, or habits and adopt other lifestyle measures that may alleviate nausea and anthracycline plus cyclophosphamide (AC) combinations (eg, vomiting (see “Eating Hints: Before, During, and After Cancer doxorubicin or epirubicin with cyclophosphamide). Although most of Treatment” from the National Cancer Institute).126 Suggestions include these drugs are also considered highly emetogenic by the Multinational eating small frequent meals, food that is “easy on the stomach”, full Association of Supportive Care in Cancer/European Society of Medical liquid foods, and food at room temperature; patients can also avoid Oncology (MASCC/ESMO) guidelines,8 the NCCN Guidelines for highly, foods that make them feel nauseous. moderately, low, and minimally emetogenic agents differ slightly based on the experience and expertise of the panel members. Prevention of Acute and Delayed Emesis To prevent acute emesis, antiemetic therapy should start before the The antiemetic regimen for these highly emetogenic drugs on day 1 administration of chemotherapy and then should cover the first 24 includes aprepitant (or fosaprepitant), dexamethasone, and a 5-HT3 hours. In the NCCN Guidelines for Antiemesis, the specific antiemetic antagonist (category 1 for the combined regimen) with or without regimens are described for highly emetogenic IV drugs, moderately lorazepam and with or without either an H2 blocker or a proton pump 23,26,89 emetogenic IV drugs, low, and minimally emetogenic IV drugs. Emesis inhibitor; note that the regimen and doses are often modified on prevention for oral chemotherapeutic agents is also described in the days 2 to 4 after chemotherapy. An alternative antiemetic regimen for NCCN Guidelines. This section discusses prechemotherapy and highly emetogenic agents on day 1 includes olanzapine, palonosetron postchemotherapy emesis prevention rather than primary treatment. and dexamethasone. Although it is not recommended as a single agent, lorazepam is a useful adjuvant because it decreases anxiety.26,111

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NCCN Guidelines Version 2.2015 NCCN Guidelines Index Antiemesis Table of Contents Antiemesis Discussion

Lorazepam is also recommended for patients who are at risk for in the setting of highly emetogenic IV chemotherapy includes anticipatory nausea and/or vomiting (see Guidelines section on olanzapine (10 mg PO days 1–4) with palonosetron (0.25 mg IV day 1 “Anticipatory Emesis Prevention/Treatment”). Antacid therapy (eg, only) and dexamethasone (20 mg IV day 1 only).121 proton pump inhibitors, H2 blockers) should be considered if patients have dyspepsia, because patients sometimes have difficulty A Canadian meta-analysis suggested that the use of 5-HT3 antagonists discriminating heartburn from nausea. (ie, ondansetron) on days 2 to 4 to prevent delayed emesis was not cost effective; however, ondansetron (when used alone) did protect against For IV regimens with high emetogenic potential, aprepitant is used at an delayed emesis in this meta-analysis.127 Palonosetron was not oral dosage of 125 mg on day 1 and then 80 mg on days 2 and 3. When assessed in these studies. The NCCN Guidelines Panel recommends given with aprepitant, dexamethasone is used at a dosage of 12 mg on the use of 5-HT3 antagonists as one of several options to prevent day 1; the dose can be oral or IV. Note that IV fosaprepitant may be delayed emesis for moderately emetogenic agents. substituted for oral aprepitant on day 1 only. If appropriate, lorazepam (0.5–2 mg either every 4 or every 6 hours on days 1–4; either oral, IV, The antiemetic regimen for moderately emetogenic IV drugs on day 1 or sublingual) may be used with each of these regimens (ie, high, includes dexamethasone and a 5-HT3 antagonist with or without moderate, or low). As previously discussed, a recent phase III lorazepam and with or without either an H2 blocker or a proton pump 5 randomized trial suggested that palonosetron is preferred over inhibitor. Aprepitant (or fosaprepitant) should be added (to granisetron for high emetic risk chemotherapy in combination with dexamethasone and a 5-HT3 antagonist) for select patients receiving dexamethasone.54 This trial has been criticized because: 1) the control certain moderate emetic risk chemotherapy (eg, carboplatin, carmustine 2 2 arm was not adequately dosed; thus, the trial “stacked the deck” in favor ≤ 250 mg/m , , , doxorubicin <60 mg/m , 2 2 of palonosetron; 2) a larger non-FDA-approved dose of palonosetron epirubicin ≤ 90 mg/m , ifosfamide <2 g/m per dose, irinotecan, or 93 was used (ie, 0.75 mg IV); and 3) aprepitant was not used in this study. methotrexate), because these agents are more emetogenic than the 7,26 The superiority of palonosetron over other available 5-HT3 antagonists other moderately emetogenic agents. IV fosaprepitant may be in preventing acute and delayed nausea and vomiting in the setting of substituted for oral aprepitant on day 1 only. Any one of the 5-HT3 high emetogenic chemotherapy was demonstrated in a recent meta- antagonists can be used, because they are all category 1 for day 1. analysis of randomized controlled trials.81 Therefore, the NCCN However, as previously mentioned, palonosetron was shown in a recent Guidelines Panel recommends palonosetron as the preferred 5-HT3 meta-analysis to be more effective than other available 5-HT3 antagonists for high emetic risk chemotherapy. The recommendation for antagonists in preventing acute and delayed nausea and vomiting for 81 palonosetron as the preferred 5-HT3 antagonist for antiemetic both high and moderately emetogenic chemotherapy agents ; hence, prophylaxis in this setting is based upon data from randomized studies the NCCN Panel recommends palonosetron as the preferred 5-HT3 (discussed earlier) with the 2-drug combination of palonosetron and antagonist in the setting of moderately emetogenic chemotherapy. dexamethasone. As previously noted, an alternative antiemetic regimen Similar to the setting of highly emetogenic chemotherapy regimens, an alternative antiemetic regimen for patients receiving moderately

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NCCN Guidelines Version 2.2015 NCCN Guidelines Index Antiemesis Table of Contents Antiemesis Discussion

emetogenic chemotherapy includes olanzapine (10 mg PO days 1–4) Postchemotherapy/Delayed Emesis Prevention with palonosetron (0.25 mg IV day 1 only) and dexamethasone (20 mg The best management for delayed emesis is prevention.133 For IV day 1 only).119,121 chemotherapeutic agents with high emetogenic potential, the prophylactic treatment (ie, dexamethasone and aprepitant) is continued The antiemetic regimen for low emetogenic IV drugs (see the NCCN through the period when delayed emesis may occur. Using this 2014 Antiemesis algorithm) includes orally administered 5-HT3 receptor strategy, prophylaxis continues for 2 to 4 days after completion of a antagonists or agents such as dexamethasone, prochlorperazine, or chemotherapy cycle. However, 5-HT3 antagonists are given on day 1 metoclopramide, with or without lorazepam, and with or without either only. an H2 blocker or a proton pump inhibitor. When using prochlorperazine or metoclopramide, patients should be monitored for dystonic For drugs with moderate emetogenic potential, postchemotherapy reactions.128-130 Diphenhydramine can be used for dystonic prevention depends on which antiemetics were used before reactions.131,132 Benztropine may be used in patients who are allergic to chemotherapy. For example, palonosetron (category 1) is only diphenhydramine.129 If appropriate, lorazepam (0.5-2 mg either every 4 administered on day 1.53 If either aprepitant or fosaprepitant was used or every 6 hours on days 1-4; either oral, IV, or sublingual) may be used on day 1, then aprepitant is continued on days 2 and 3. with each of these regimens (ie, high, moderate, or low). Recently, a randomized double-blind trial was conducted to evaluate the The emetogenic potential of oral chemotherapeutic agents is shown in effectiveness of 4 different antiemetic regimens in preventing delayed the NCCN Guidelines. Antiemetic prophylaxis is recommended for the nausea in patients receiving moderate or high emetic risk chemotherapy following oral agents: altretamine, busulfan (≥ 4 mg/day), crizotinib, (N=1021; n=944 evaluable).134 The 4 regimens evaluated included the cyclophosphamide (≥100 mg/m2/day), estramustine, etoposide, following: Group 1 with palonosetron and dexamethasone day 1, lomustine (single day), mitotane, procarbazine, temozolomide (> 75 prochlorperazine days 2, 3; Group 2 with granisetron and mg/m2/day or ≤ 75 mg/m2/day with concurrent radiotherapy) and dexamethasone day 1, prochlorperazine days 2, 3; Group 3 with vismodegib. For high or moderate emetic risk oral agents, palonosetron, aprepitant and dexamethasone day 1, aprepitant and recommended prophylaxis includes oral 5-HT3 antagonists (such as dexamethasone days 2, 3; and Group 4 with palonosetron and granisetron or ondansetron) with or without lorazepam and with or dexamethasone day 1, prochlorperazine and dexamethasone days 2, 3. without either an H2 blocker or a proton pump inhibitor. For low or Severity of nausea was measured using a 7-point semantic rating scale; minimal emetic risk oral agents, recommended prophylaxis includes oral mean and maximum severity scores were obtained from measurements 5-HT3 antagonists, metoclopramide, prochlorperazine, or haloperidol taken throughout day 1 (for acute nausea) and throughout days 2 and 3 with or without lorazepam and with or without either an H2 blocker or a (for delayed nausea). The trial was designed to address several specific proton pump inhibitor; prophylaxis is given before chemotherapy is research objectives for controlling delayed nausea, including the started and then on an as needed basis only (ie, PRN). comparison of palonosetron with granisetron (Group 1 vs. Group 2), activity of adding dexamethasone to prochlorperazine on days 2, 3

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NCCN Guidelines Version 2.2015 NCCN Guidelines Index Antiemesis Table of Contents Antiemesis Discussion

(Group 1 vs. Group 4), and activity of aprepitant compared with Perugia Consensus Conference on Antiemetic Therapy held in June prochlorperazine when both agents are combined with palonosetron 2009. and dexamethasone (Group 3 vs. Group 4).134 Data from this trial showed no significant differences between palonosetron and Breakthrough Treatment granisetron in the mean or maximum severity of delayed nausea, when Breakthrough emesis presents a difficult situation, because refractory these agents were used with dexamethasone and prochlorperazine. ongoing nausea and/or vomiting is often challenging to reverse (see Similarly, no significant differences were observed between aprepitant Guidelines section on “Principles for Managing Breakthrough Emesis”). and prochlorperazine in controlling delayed nausea, when these agents Generally, it is much easier to prevent nausea and/or vomiting than to were combined with palonosetron and dexamethasone.134 This trial also treat it. Thus, routine around-the-clock administration of antiemetics showed that the addition of dexamethasone to prochlorperazine on should be strongly considered to prevent emesis, rather than PRN (as days 2 and 3 (for a regimen with palonosetron and dexamethasone on required) dosing. The general principle of breakthrough treatment is to day 1) improved the severity of both mean and maximum delayed give an additional agent as needed from a different drug class.23 nausea compared with prochlorperazine alone. However, no single treatment is better than another for managing breakthrough emesis. Some patients may require several agents using The antiemetic regimens in the NCCN Guidelines include different different mechanisms of action. The oral route may not be feasible 23,26,133 options on days 2 to 3 for moderate emetic risk agents. There are because of ongoing vomiting; therefore, rectal or IV therapy is often 3 possible regimens on days 2 to 3 including: 1) aprepitant (if used on required. Nasal sprays might be useful for treatment of breakthrough day 1); 2) dexamethasone; or 3) 5-HT3 antagonist, such as emesis, because they provide acute delivery of agents.136,137 Multiple 133 ondansetron, granisetron, or dolasetron. Each of these regimens may concurrent agents, perhaps in alternating schedules or by alternating also include the following: ± lorazepam and ± either an H2 blocker or a routes, may be necessary. proton pump inhibitor. It is important to note that the doses of both aprepitant (80 mg PO) and dexamethasone (8 mg PO or IV) are Miscellaneous agents (eg, haloperidol, metoclopramide, olanzapine, decreased when used on days 2 to 3 (when compared with the doses scopolamine transdermal patch), corticosteroids, and agents such as given on day 1). Note that palonosetron is not given on days 2 to 3. lorazepam may be incorporated for breakthrough treatment. In a recent Fosaprepitant is also not given on days 2 to 3. randomized double-blind phase III study, the effectiveness of olanzapine (10 mg/day PO for 3 days) as treatment for breakthrough The NCCN, MASCC, and American Society of Clinical Oncology emesis was compared with metoclopramide in patients treated with (ASCO) guidelines all recommend using aprepitant to prevent delayed highly emetogenic chemotherapy regimens who developed 8,26,135 nausea and/or vomiting when giving AC regimens. Note that the breakthrough emesis or nausea despite antiemetic prophylaxis MASCC guidelines are updated on a biannual basis following the (comprising palonosetron, dexamethasone and fosaprepitant; N=112; publication of the initial consensus guidelines, which were based on the n=108 evaluable).138,139 Patients were observed for emesis and nausea

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during the 72 hours after treatment with olanzapine or metoclopramide. irradiation is associated with the highest risk for emesis and that upper During this observation period, a higher proportion of patients had no abdominal radiation is associated with moderate risk.24 A recent meta- emesis (70% vs. 31%; P<0.01) and no nausea (68% vs. 23%; P<0.01) analysis suggests that 5-HT3 antagonists are the preferred agents for with olanzapine than metoclopramide.139 Thus, olanzapine was more preventing radiation-induced vomiting.142 effective in controlling breakthrough emesis and nausea compared with metoclopramide in this patient population. Dronabinol and nabilone Patients undergoing radiation therapy to the upper abdomen may (which are cannabinoids) are approved by the FDA for nausea and receive antiemetic prophylaxis with oral ondansetron or oral granisetron, 8,24 vomiting in patients who have not responded to conventional antiemetic with or without oral dexamethasone. A randomized study compared agents. Adequate hydration or fluid repletion should be ensured, and oral ondansetron with placebo in patients receiving daily fractionated any possible electrolyte abnormalities should be assessed and radiotherapy including the abdomen. In this study, 67% of patients corrected. Before administering the next cycle of chemotherapy, the given ondansetron had complete control of emesis compared with 45% 143 patient should be reassessed for other possible non-chemotherapy- of patients who received placebo (P<0.05). A study showed that the related reasons for breakthrough emesis with the current cycle (eg, addition of oral dexamethasone (4 mg daily) to the ondansetron brain metastases, electrolyte abnormalities, tumor infiltration of the regimen decreases emesis and nausea, although the effect is 144 bowel or other GI abnormality, and other comorbidities; see Guidelines modest. Another randomized study in patients receiving radiotherapy section on “Principles for Managing Breakthrough Emesis”). to the upper abdomen found that oral granisetron decreased emesis and nausea when compared with placebo.145 In addition, before the next cycle of chemotherapy, the antiemetic regimen (both the day 1 and postchemotherapeutic) that did not protect Patients undergoing total body irradiation may receive antiemetic the patient during the present cycle should be assessed and prophylaxis with either ondansetron or granisetron; either agent can be 8,24,146 alternatives should be considered (see Guidelines section on “Principles given with or without oral dexamethasone. Treatment of for Managing Breakthrough Emesis”). Because patients sometimes breakthrough radiation-induced emesis is similar to chemotherapy- have difficulty discriminating heartburn from nausea, use of antacid induced emesis. Patients who do not receive primary prophylaxis and therapy (eg, proton pump inhibitors, H2 blockers) should be considered. experience breakthrough nausea and/or vomiting may be treated with ondansetron, similar to primary prophylaxis. Radiation-Induced Nausea and/or Vomiting Anticipatory Nausea and/or Vomiting Prophylaxis for radiation-induced nausea and/or vomiting is based on the site of radiation and whether it is combined with About 20% of patients develop anticipatory nausea and/or vomiting. chemotherapy.24,140,141 When radiation is combined with chemotherapy, However, the rate of anticipatory nausea and/or vomiting appears to be prophylaxis is dictated by the emetogenic potential of the chemotherapy decreasing (when compared with older studies) with current use of 8 regimen. Recent MASCC/ESMO guidelines state that total body more effective antiemetic regimens. The most effective way to treat anticipatory nausea and/or vomiting is to prevent it by using optimal

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antiemetic therapy during every cycle of treatment.23,147,148 Behavioral Guidelines section on “Principles for Managing Multiday Emetogenic therapy has been used in patients with anticipatory nausea and/or Chemotherapy Regimens”). vomiting.149-154 Systematic desensitization may also be helpful.150 Hypnosis with guided imagery is another behavioral technique that has For antiemetic prophylaxis of multiday emetogenic chemotherapy shown some success in treating this condition.151 regimens (eg, cisplatin-containing regimens), the combination of a 5- HT3 antagonist with dexamethasone has been the standard The antianxiety agents lorazepam and alprazolam have been combined treatment.8,23,135 Dexamethasone should be administered once daily with antiemetics for anticipatory nausea and/or vomiting.148,155,156 The either orally or intravenously for every day of moderately or highly usual starting dose of alprazolam for anxiety is 0.25 to 0.5 mg orally 3 emetogenic chemotherapy and for 2 to 3 days after chemotherapy for times daily, beginning on the night before treatment. In elderly patients, regimens that are likely to cause significant delayed emesis. However, patients with debilitating disease, and patients with advanced liver dexamethasone should not be added when the chemotherapy regimen disease, the usual starting dose of alprazolam is 0.25 mg orally 2 or 3 already includes a corticosteroid. Steroids should also be avoided when times daily for treatment of anxiety.157 This dose may be gradually using regimens containing interleukin-2 (IL-2, aldesleukin) and increased if needed. Note that the elderly are especially sensitive to the interferon.163 effects of benzodiazepines. The dose should be gradually reduced when decreasing or discontinuing alprazolam therapy. A 5-HT3 receptor antagonist should be administered each day before the first dose of moderately or highly emetogenic chemotherapy. Managing Multiday Emetogenic Chemotherapy Intravenous palonosetron may be used before the start of a 3-day Regimens chemotherapy regimen instead of multiple daily doses of oral or 164,165 Patients receiving multiple day (ie, multiday) chemotherapy are at risk intravenous 5-HT3 receptor antagonists. Repeat dosing of for both acute and delayed nausea and/or vomiting based on the palonosetron (0.25 mg IV) is likely to be safe, based on the dose emetogenic potential of the individual chemotherapy agents and their ranging phase II trial and the 3 phase III trials using palonosetron as a 51-53,166 sequence.23,158-162 It is difficult to recommend a specific antiemetic single fixed dose (0.75 mg IV). Compared to the approved dose of regimen for each day, especially because acute and delayed emesis palonosetron of 0.25 mg IV, these higher doses were not associated may overlap after the initial day of chemotherapy until the last day of with significantly different adverse events. chemotherapy. The period of risk for delayed emesis following The need for repeat dosing with palonosetron, either daily or less completion of chemotherapy also depends on the specific regimen and frequently, in the setting of multiday chemotherapy is not yet known. In the emetogenic potential of the last chemotherapy agent administered one study, patients receiving highly emetogenic multiday cisplatin- in the regimen. For multi-drug regimens, antiemetic therapy should be based chemotherapy for testicular cancer (N=41) received multiday selected based on the drug with the highest emetic risk. General dosing of palonosetron (0.25 mg IV on days 1, 3, and 5) and principles for managing multiday emetogenic chemotherapy regimens dexamethasone, which prevented nausea and emesis in most patients recommended by the panel are described in the algorithm (see

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on days 1 to 5 (51%) and on days 6 to 9 (83%); the most common days 1–8) was evaluated in patients with germ line tumors undergoing adverse events were mild headache and constipation.167 A recent study chemotherapy cycles with 5-day cisplatin-based regimens (N=50).170 assessed palonosetron given for 1, 2, or 3 days in combination with During cycle 1 of chemotherapy, 96% of patients had no emesis on day dexamethasone for patients receiving multiday high-dose chemotherapy 1 and 82% had no emesis during days 1 to 7. In addition, 71% had no prior to stem cell transplantation for multiple myeloma (N=73); during nausea on day 1 of cycle 1, and 27% had no nausea during days 1 to 7. the 7-day emesis prevention period, about 40-45% of patients had no Over 80% of patients had no emesis on any given day of any given emesis (with no differences observed between palonosetron treatment chemotherapy cycle. No unexpected or serious adverse events were groups), and no serious adverse events were reported. However, even reported.170 In a recent double-blind, randomized, placebo-controlled among the patients who received either 2 or 3 days of palonosetron, phase III cross-over trial, the efficacy of adding aprepitant (versus only 20% had a complete response (ie, emesis free without rescue placebo) to an antiemetic regimen with 5-HT3 receptor antagonist and medication).168 Another study found that a palonosetron/dexamethasone dexamethasone was evaluated in patients with testicular cancer regimen appeared to be more effective for multiday chemotherapy than undergoing 2 cycles of a 5-day cisplatin combination chemotherapy an ondansetron/dexamethasone regimen; patients received a second regimen (N=71; n=69 evaluable).171 Patients were randomized to dose of palonosetron for breakthrough emesis, which was effective in receive aprepitant (125 mg PO day 3, 80 mg PO days 4–7) or placebo, 67% of patients who experienced nausea or vomiting.164 Further studies combined with a 5-HT3 antagonist (days 1–5) and dexamethasone (20 are needed to define whether a need exists for repeat dosing of mg days 1, 2) during the first cycle, and then crossed over to the palonosetron in the setting of multiday chemotherapy. opposite antiemetic regimen during the second cycle of chemotherapy. Thus, patients served as their own controls after receiving either The potential role of NK-1 antagonists in the antiemetic management of aprepitant or placebo for cycle 1. Palonosetron was excluded from the multiday chemotherapy regimens has been investigated in several options for 5-HT3 antagonists due to its longer half-life.171 The primary studies. In one study, the addition of the NK-1 antagonist aprepitant to endpoint of the study was CR (no emetic episodes and no rescue granisetron and dexamethasone was evaluated in patients receiving medication) during the overall study period (days 1–8). The CR rate for multiday high and moderate emetogenic chemotherapy (N=78); in this the overall study period was significantly higher with aprepitant study, the 3-drug antiemetic regimen was given during chemotherapy, compared with placebo (42% vs. 13%; P<0.001). The CR rates were and aprepitant and dexamethasone was given for an additional 2 days also higher with aprepitant during the acute phase (days 1–5; 47% vs. 169 following chemotherapy. CR (during the time period from day 1 until 5 15%; P<0.001) and delayed phase (days 6–8; 63% vs. 35%; days after chemotherapy) was observed in 58% and 73% of patients P<0.001).171 No statistically significant differences were observed 169 who received high and moderate emetogenic regimens, respectively. between treatment regimens in terms of nausea (based on patient- In a recent multicenter phase II study, an extended 7-day regimen with reported visual analog scale). Importantly, no increase in toxicity with aprepitant (125 mg PO day 1, 80 mg PO days 2–7) combined with a 5- aprepitant compared with placebo was reported.171 HT3 receptor antagonist (days 1–5) and dexamethasone (8 mg PO

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NCCN Guidelines Version 2.2015 NCCN Guidelines Index Antiemesis Table of Contents Antiemesis Discussion

Aprepitant may be used for multiday chemotherapy regimens likely to be highly emetogenic and associated with significant risk for delayed nausea and emesis. As per the labeled indication, aprepitant should be administered 125 mg orally 1 hour prior to chemotherapy on day 1, along with a 5-HT3 receptor antagonist and dexamethasone. Aprepitant 80 mg should be administered daily on days 2 and 3 after the start of chemotherapy along with dexamethasone.158 Repeated dosing of aprepitant over multiple cycles of cisplatin-based chemotherapy was shown to be feasible and well tolerated; importantly, protection from emesis and from significant nausea was maintained during the subsequent cycles of emetogenic chemotherapy.95,158 Based on phase II data, aprepitant 80 mg may be safely administered beyond day 3 of initiating chemotherapy.96,170 Alternatively, for highly emetogenic chemotherapy regimens, fosaprepitant 150 mg IV with dexamethasone may be given on day 1 with no need for oral aprepitant on days 2 and 3 with recommended dosing of dexamethasone.

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NCCN Guidelines Version 2.2015 NCCN Guidelines Index Antiemesis Table of Contents Antiemesis Discussion

References conference. Ann Oncol 2010;21 Suppl 5:v232-243. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20555089. 1. Laszlo J. Emesis as limiting toxicity in cancer chemotherapy. In: Laszlo J, ed. Antiemetics and Cancer Chemotherapy. Baltimore, 9. Grunberg SM, Warr D, Gralla RJ, et al. Evaluation of new Maryland: Williams & Wilkins; 1983:1-5. antiemetic agents and definition of antineoplastic agent emetogenicity- state of the art. Support Care Cancer 2010;19:S43-47. Available at: 2. Ingle RJ, Burish TG, Wallston KA. Conditionability of cancer http://www.ncbi.nlm.nih.gov/pubmed/20972805. chemotherapy patients. Oncol Nurs Forum 1984;11:97-9102. Available at: http://www.ncbi.nlm.nih.gov/pubmed/6566342. 10. Roscoe JA, Morrow GR, Colagiuri B, et al. Insight in the prediction of chemotherapy-induced nausea. Support Care Cancer 2010;18:869- 3. Mitchell EP. Gastrointestinal toxicity of chemotherapeutic agents. 876. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19701781. Semin Oncol 1992;19:566-579. Available at: http://www.ncbi.nlm.nih.gov/pubmed/1411654. 11. Craig JB, Powell BL. The management of nausea and vomiting in clinical oncology. Am J Med Sci 1987;293:34-44. Available at: 4. Richardson JL, Marks G, Levine A. The influence of symptoms of http://www.ncbi.nlm.nih.gov/pubmed/3544842. disease and side effects of treatment on compliance with cancer therapy. J Clin Oncol 1988;6:1746-1752. Available at: 12. Borison HL, Wang SC. Physiology and pharmacology of vomiting. http://www.ncbi.nlm.nih.gov/pubmed/3183704. Pharmacol Rev 1953;5:193-230. Available at: http://www.ncbi.nlm.nih.gov/pubmed/13064033. 5. Herrstedt J. Antiemetics: an update and the MASCC guidelines applied in clinical practice. Nat Clin Pract Oncol 2008;5:32-43. 13. Seigel LJ, Longo DL. The control of chemotherapy-induced Available at: http://www.ncbi.nlm.nih.gov/pubmed/18097455. emesis. Ann Intern Med 1981;95:352-359. Available at: http://www.ncbi.nlm.nih.gov/pubmed/7023313. 6. Hesketh PJ, Grunberg SM, Herrstedt J, et al. Combined data from two phase III trials of the NK1 antagonist aprepitant plus a 5HT 3 14. Dodds LJ. The control of cancer chemotherapy-induced nausea antagonist and a corticosteroid for prevention of chemotherapy- and vomiting. J Clin Hosp Pharm 1985;10:143-166. Available at: induced nausea and vomiting: effect of gender on treatment response. http://www.ncbi.nlm.nih.gov/pubmed/2862166. Support Care Cancer 2006;14:354-360. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16450086. 15. Aapro MS. Palonosetron as an anti-emetic and anti-nausea agent in oncology. Ther Clin Risk Manag 2007;3:1009-1020. Available at: 7. Hesketh PJ, Kris MG, Grunberg SM, et al. Proposal for classifying http://www.ncbi.nlm.nih.gov/pubmed/18516316. the acute emetogenicity of cancer chemotherapy. J Clin Oncol 1997;15:103-109. Available at: 16. Grunberg SM, Deuson RR, Mavros P, et al. Incidence of http://www.ncbi.nlm.nih.gov/pubmed/8996130. chemotherapy-induced nausea and emesis after modern antiemetics. Cancer 2004;100:2261-2268. Available at: 8. Roila F, Herrstedt J, Aapro M, et al. Guideline update for MASCC http://www.ncbi.nlm.nih.gov/pubmed/15139073. and ESMO in the prevention of chemotherapy- and radiotherapy- induced nausea and vomiting: results of the Perugia consensus 17. Hickok JT, Roscoe JA, Morrow GR, et al. 5-Hydroxytryptamine- receptor antagonists versus prochlorperazine for control of delayed

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24. Feyer PC, Maranzano E, Molassiotis A, et al. Radiotherapy- 32. Koeller JM, Aapro MS, Gralla RJ, et al. Antiemetic guidelines: induced nausea and vomiting (RINV): MASCC/ESMO guideline for creating a more practical treatment approach. Support Care Cancer

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33. Hesketh PJ, Gandara DR. Serotonin antagonists: a new class of 40. Marty M. A comparative study of the use of granisetron, a selective antiemetic agents. J Natl Cancer Inst 1991;83:613-620. Available at: 5-HT3 antagonist, versus a standard anti-emetic regimen of http://www.ncbi.nlm.nih.gov/pubmed/1850806. plus dexamethasone in the treatment of cytostatic- induced emesis. The Granisetron Study Group. Eur J Cancer 1990;26 34. Andrews PL, Bhandari P, Davey PT, et al. Are all 5-HT3 receptor Suppl 1:S28-32. Available at: antagonists the same? Eur J Cancer 1992;28A Suppl 1:2-6. Available http://www.ncbi.nlm.nih.gov/pubmed/2169783. at: http://www.ncbi.nlm.nih.gov/pubmed/1320915. 41. Marty M, Pouillart P, Scholl S, et al. Comparison of the 5- 35. Grunberg SM, Koeller JM. Palonosetron: a unique 5-HT3-receptor hydroxytryptamine3 (serotonin) antagonist ondansetron (GR 38032F) antagonist for the prevention of chemotherapy-induced emesis. Expert with high-dose metoclopramide in the control of cisplatin-induced Opin Pharmacother 2003;4:2297-2303. Available at: emesis. N Engl J Med 1990;322:816-821. Available at: http://www.ncbi.nlm.nih.gov/pubmed/14640928. http://www.ncbi.nlm.nih.gov/pubmed/2137902.

36. Grunberg SM, Stevenson LL, Russell CA, McDermed JE. Dose 42. Soukop M. A comparison of two dose levels of granisetron in ranging phase I study of the serotonin antagonist GR38032F for patients receiving high-dose cisplatin. The Granisetron Study Group. prevention of cisplatin-induced nausea and vomiting. J Clin Oncol Eur J Cancer 1990;26 Suppl 1:S15-19. Available at: 1989;7:1137-1141. Available at: http://www.ncbi.nlm.nih.gov/pubmed/2169779. http://www.ncbi.nlm.nih.gov/pubmed/2526864. 43. Roila F, Tonato M, Cognetti F, et al. Prevention of cisplatin- 37. Chevallier B. Efficacy and safety of granisetron compared with induced emesis: a double-blind multicenter randomized crossover high-dose metoclopramide plus dexamethasone in patients receiving study comparing ondansetron and ondansetron plus dexamethasone. high-dose cisplatin in a single-blind study. The Granisetron Study J Clin Oncol 1991;9:675-678. Available at: Group. Eur J Cancer 1990;26 Suppl 1:S33-36. Available at: http://www.ncbi.nlm.nih.gov/pubmed/1829757. http://www.ncbi.nlm.nih.gov/pubmed/2169784. 44. Fraschini G. Antiemetic activity of ondansetron in cancer patients 38. Cupissol DR, Serrou B, Caubel M. The efficacy of granisetron as a receiving non-cisplatin chemotherapy. Semin Oncol 1992;19:41-47. prophylactic anti-emetic and intervention agent in high-dose cisplatin- Available at: http://www.ncbi.nlm.nih.gov/pubmed/1387249. induced emesis. Eur J Cancer 1990;26 Suppl 1:23-27. Available at: http://www.ncbi.nlm.nih.gov/pubmed/2169782. 45. Kamanabrou D. Intravenous granisetron--establishing the optimal dose. The Granisetron Study Group. Eur J Cancer 1992;28A Suppl 39. De Mulder PH, Seynaeve C, Vermorken JB, et al. Ondansetron 1:6-11. Available at: http://www.ncbi.nlm.nih.gov/pubmed/1320919. compared with high-dose metoclopramide in prophylaxis of acute and delayed cisplatin-induced nausea and vomiting. A multicenter, 46. Sledge GW, Einhorn L, Nagy C, House K. Phase III double-blind randomized, double-blind, crossover study. Ann Intern Med comparison of intravenous ondansetron and metoclopramide as antiemetic therapy for patients receiving multiple-day cisplatin-based

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chemotherapy. Cancer 1992;70:2524-2528. Available at: 53. Gralla R, Lichinitser M, Van Der Vegt S, et al. Palonosetron http://www.ncbi.nlm.nih.gov/pubmed/1423181. improves prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy: results of a double- 47. Chevallier B. The control of acute cisplatin-induced emesis--a blind randomized phase III trial comparing single doses of comparative study of granisetron and a combination regimen of high- palonosetron with ondansetron. Ann Oncol 2003;14:1570-1577. dose metoclopramide and dexamethasone. Granisetron Study Group. Available at: http://www.ncbi.nlm.nih.gov/pubmed/14504060. Br J Cancer 1993;68:176-180. Available at: http://www.ncbi.nlm.nih.gov/pubmed/8391304. 54. Saito M, Aogi K, Sekine I, et al. Palonosetron plus dexamethasone versus granisetron plus dexamethasone for prevention of nausea and 48. Navari RM, Kaplan HG, Gralla RJ, et al. Efficacy and safety of vomiting during chemotherapy: a double-blind, double-dummy, granisetron, a selective 5-hydroxytryptamine-3 receptor antagonist, in randomised, comparative phase III trial. Lancet Oncol 2009;10:115- the prevention of nausea and vomiting induced by high-dose cisplatin. 124. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19135415. J Clin Oncol 1994;12:2204-2210. Available at: http://www.ncbi.nlm.nih.gov/pubmed/7931490. 55. Miura S, Watanabe S, Sato K, et al. The efficacy of triplet antiemetic therapy with 0.75 mg of palonosetron for chemotherapy- 49. Riviere A. Dose finding study of granisetron in patients receiving induced nausea and vomiting in lung cancer patients receiving highly high-dose cisplatin chemotherapy. The Granisetron Study Group. Br J emetogenic chemotherapy. Support Care Cancer 2013. Available at: Cancer 1994;69:967-971. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23644992. http://www.ncbi.nlm.nih.gov/pubmed/8180032. 56. Grote T, Hajdenberg J, Cartmell A, et al. Combination therapy for 50. Rojas C, Thomas AG, Alt J, et al. Palonosetron triggers 5-HT(3) chemotherapy-induced nausea and vomiting in patients receiving receptor internalization and causes prolonged inhibition of receptor moderately emetogenic chemotherapy: palonosetron, dexamethasone, function. Eur J Pharmacol 2010;626:193-199. Available at: and aprepitant. J Support Oncol 2006;4:403-408. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19836386. http://www.ncbi.nlm.nih.gov/pubmed/17004515.

51. Aapro MS, Grunberg SM, Manikhas GM, et al. A phase III, double- 57. Grunberg SM, Dugan M, Muss H, et al. Effectiveness of a single- blind, randomized trial of palonosetron compared with ondansetron in day three-drug regimen of dexamethasone, palonosetron, and preventing chemotherapy-induced nausea and vomiting following aprepitant for the prevention of acute and delayed nausea and highly emetogenic chemotherapy. Ann Oncol 2006;17:1441-1449. vomiting caused by moderately emetogenic chemotherapy. Support Available at: http://www.ncbi.nlm.nih.gov/pubmed/16766588. Care Cancer 2009;17:589-594. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19037667. 52. Eisenberg P, Figueroa-Vadillo J, Zamora R, et al. Improved prevention of moderately emetogenic chemotherapy-induced nausea 58. Longo F, Mansueto G, Lapadula V, et al. Palonosetron plus 3-day and vomiting with palonosetron, a pharmacologically novel 5-HT3 aprepitant and dexamethasone to prevent nausea and vomiting in receptor antagonist: results of a phase III, single-dose trial versus patients receiving highly emetogenic chemotherapy. Support Care dolasetron. Cancer 2003;98:2473-2482. Available at: Cancer 2011;19:1159-1164. Available at: http://www.ncbi.nlm.nih.gov/pubmed/14635083. http://www.ncbi.nlm.nih.gov/pubmed/20552375.

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59. Yang LP, Scott LJ. Palonosetron: in the prevention of nausea and 66. Jantunen IT, Muhonen TT, Kataja VV, et al. 5-HT3 receptor vomiting. Drugs 2009;69:2257-2278. Available at: antagonists in the prophylaxis of acute vomiting induced by http://www.ncbi.nlm.nih.gov/pubmed/19852528. moderately emetogenic chemotherapy--a randomised study. Eur J Cancer 1993;29A:1669-1672. Available at: 60. United States Food and Drug Administration. Anzemet (dolasetron http://www.ncbi.nlm.nih.gov/pubmed/8398291. mesylate): Drug Safety Communication - Reports of Abnormal Heart Rhythms. 2010. Available at: 67. Martoni A, Angelelli B, Guaraldi M, et al. An open randomised http://www.fda.gov/Drugs/DrugSafety/ucm237081.htm. Accessed June cross-over study on granisetron versus ondansetron in the prevention 2011. of acute emesis induced by moderate dose cisplatin-containing regimens. Eur J Cancer 1996;32A:82-85. Available at: 61. United States Food and Drug Administration. FDA Drug Safety http://www.ncbi.nlm.nih.gov/pubmed/8695248. Communication: New information regarding QT prolongation with ondansetron (Zofran). 2012. Available at: 68. Gebbia V, Cannata G, Testa A, et al. Ondansetron versus http://www.fda.gov/Drugs/DrugSafety/ucm310190.htm. Accessed granisetron in the prevention of chemotherapy-induced nausea and September 2012. vomiting. Results of a prospective randomized trial. Cancer 1994;74:1945-1952. Available at: 62. ProStrakan Inc. Prescribing Information. Sancuso (Granisetron http://www.ncbi.nlm.nih.gov/pubmed/8082100. Transdermal System). 2008. Available at: http://www.sancuso.com/forms/SANCUSO-Full_PI.pdf. Accessed June 69. Mantovani G, Maccio A, Bianchi A, et al. Comparison of 2011. granisetron, ondansetron, and in the prophylaxis of acute nausea and vomiting induced by cisplatin for the treatment of head 63. Boccia RV, Gordan LN, Clark G, et al. Efficacy and tolerability of and neck cancer: a randomized controlled trial. Cancer 1996;77:941- transdermal granisetron for the control of chemotherapy-induced 948. Available at: http://www.ncbi.nlm.nih.gov/pubmed/8608488. nausea and vomiting associated with moderately and highly emetogenic multi-day chemotherapy: a randomized, double-blind, 70. Noble A, Bremer K, Goedhals L, et al. A double-blind, randomised, phase III study. Support Care Cancer 2010. Available at: crossover comparison of granisetron and ondansetron in 5-day http://www.ncbi.nlm.nih.gov/pubmed/20835873. fractionated chemotherapy: assessment of efficacy, safety and patient preference. The Granisetron Study Group. Eur J Cancer 64. Howell J, Smeets J, Drenth HJ, Gill D. Pharmacokinetics of a 1994;30A:1083-1088. Available at: granisetron transdermal system for the treatment of chemotherapy- http://www.ncbi.nlm.nih.gov/pubmed/7654434. induced nausea and vomiting. J Oncol Pharm Pract 2009;15:223-231. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19304880. 71. Ruff P, Paska W, Goedhals L, et al. Ondansetron compared with granisetron in the prophylaxis of cisplatin-induced acute emesis: a 65. Bonneterre J, Hecquet B. Granisetron (IV) compared with multicentre double-blind, randomised, parallel-group study. The ondansetron (IV plus oral) in the prevention of nausea and vomiting Ondansetron and Granisetron Emesis Study Group. Oncology induced by moderately-emetogenic chemotherapy. A cross-over study. 1994;51:113-118. Available at: Bull Cancer 1995;82:1038-1043. Available at: http://www.ncbi.nlm.nih.gov/pubmed/8265095. http://www.ncbi.nlm.nih.gov/pubmed/8745670.

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NCCN Guidelines Version 2.2015 NCCN Guidelines Index Antiemesis Table of Contents Antiemesis Discussion

72. Ondansetron versus granisetron, both combined with 78. Lofters WS, Pater JL, Zee B, et al. Phase III double-blind dexamethasone, in the prevention of cisplatin-induced emesis. Italian comparison of dolasetron mesylate and ondansetron and an Group of Antiemetic Research. Ann Oncol 1995;6:805-810. Available evaluation of the additive role of dexamethasone in the prevention of at: http://www.ncbi.nlm.nih.gov/pubmed/8589019. acute and delayed nausea and vomiting due to moderately emetogenic chemotherapy. J Clin Oncol 1997;15:2966-2973. Available 73. Navari R, Gandara D, Hesketh P, et al. Comparative clinical trial of at: http://www.ncbi.nlm.nih.gov/pubmed/9256141. granisetron and ondansetron in the prophylaxis of cisplatin-induced emesis. The Granisetron Study Group. J Clin Oncol 1995;13:1242- 79. Jordan K, Hinke A, Grothey A, et al. A meta-analysis comparing 1248. Available at: http://www.ncbi.nlm.nih.gov/pubmed/7738628. the efficacy of four 5-HT3-receptor antagonists for acute chemotherapy-induced emesis. Support Care Cancer 2007;15:1023- 74. Stewart A, McQuade B, Cronje JD, et al. Ondansetron compared 1033. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17205281. with granisetron in the prophylaxis of cyclophosphamide-induced emesis in out-patients: a multicentre, double-blind, double-dummy, 80. Billio A, Morello E, Clarke MJ. Serotonin receptor antagonists for randomised, parallel-group study. Emesis Study Group for highly emetogenic chemotherapy in adults. Cochrane Database Syst Ondansetron and Granisetron in Breast Cancer Patients. Oncology Rev 2010:CD006272. Available at: 1995;52:202-210. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20091591. http://www.ncbi.nlm.nih.gov/pubmed/7715904. 81. Botrel TE, Clark OA, Clark L, et al. Efficacy of palonosetron (PAL) 75. Audhuy B, Cappelaere P, Martin M, et al. A double-blind, compared to other serotonin inhibitors (5-HT(3)R) in preventing randomised comparison of the anti-emetic efficacy of two intravenous chemotherapy-induced nausea and vomiting (CINV) in patients doses of dolasetron mesilate and granisetron in patients receiving high receiving moderately or highly emetogenic (MoHE) treatment: dose cisplatin chemotherapy. Eur J Cancer 1996;32A:807-813. systematic review and meta-analysis. Support Care Cancer Available at: http://www.ncbi.nlm.nih.gov/pubmed/9081358. 2011;19:823-832. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20495832. 76. Fauser AA, Duclos B, Chemaissani A, et al. Therapeutic equivalence of single oral doses of dolasetron mesilate and multiple 82. Aapro M, Fabi A, Nole F, et al. Double-blind, randomised, doses of ondansetron for the prevention of emesis after moderately controlled study of the efficacy and tolerability of palonosetron plus emetogenic chemotherapy. European Dolasetron Comparative Study dexamethasone for 1 day with or without dexamethasone on days 2 Group. Eur J Cancer 1996;32A:1523-1529. Available at: and 3 in the prevention of nausea and vomiting induced by moderately http://www.ncbi.nlm.nih.gov/pubmed/8911112. emetogenic chemotherapy. Ann Oncol 2010;21:1083-1088. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20080830. 77. Hesketh P, Navari R, Grote T, et al. Double-blind, randomized comparison of the antiemetic efficacy of intravenous dolasetron 83. Huang JQ, Zheng GF, Deuson R, et al. Do 5-hydroxytryptamine3 mesylate and intravenous ondansetron in the prevention of acute receptor antagonists (5-HT3) improve the antiemetic effect of cisplatin-induced emesis in patients with cancer. Dolasetron dexamethasone for preventing delayed chemotherapy-induced nausea Comparative Chemotherapy-induced Emesis Prevention Group. J Clin and vomiting (CINV)? A meta-analysis of randomized controlled trials Oncol 1996;14:2242-2249. Available at: [abstract]. J Clin Oncol 2004;22(Suppl 14): Abstract 6037. Available http://www.ncbi.nlm.nih.gov/pubmed/8708713. at: http://meeting.ascopubs.org/cgi/content/abstract/22/14_suppl/6037.

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NCCN Guidelines Version 2.2015 NCCN Guidelines Index Antiemesis Table of Contents Antiemesis Discussion

84. United States Food and Drug Administration. FDA Drug Safety 90. Poli-Bigelli S, Rodrigues-Pereira J, Carides AD, et al. Addition of Communication: Abnormal heart rhythms may be associated with use the neurokinin 1 receptor antagonist aprepitant to standard antiemetic of Zofran (ondansetron). 2011. Available at: therapy improves control of chemotherapy-induced nausea and http://www.fda.gov/Drugs/DrugSafety/ucm271913.htm. Accessed vomiting. Results from a randomized, double-blind, placebo-controlled September 2012. trial in Latin America. Cancer 2003;97:3090-3098. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12784346. 85. Baltzer L, Kris MG, Hinkley L, et al. Reversible electrocardiographic interval prolongations following the specific 91. Tremont-Lukats IW, Gonzalez-Barboteo J, Bruera E, Brescia FJ. serotonin antagonists ondanestron (OND) and dolasetron mesylate Meta-analysis of neurokinin-1 receptor antagonists (NK-1 RA) for (DM): a possible drug class effect without sequelae? [abstract]. J Clin chemotherapy-induced nausea and vomiting (CINV) [abstract]. J Clin Oncol 1994;13:Abstract 1489. Available at: Oncol 2004;22(Suppl 14):Abstract 8047. Available at: http://meeting.ascopubs.org/cgi/content/abstract/22/14_suppl/8047. 86. Gonullu G, Demircan S, Demirag MK, et al. Electrocardiographic findings of palonosetron in cancer patients. Support Care Cancer 92. Dos Santos LV, Souza FH, Brunetto AT, et al. Neurokinin-1 2012;20:1435-1439. Available at: receptor antagonists for chemotherapy-induced nausea and vomiting: http://www.ncbi.nlm.nih.gov/pubmed/21773677. a systematic review. J Natl Cancer Inst 2012;104:1280-1292. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22911671. 87. Leonard MC, Militello ML. 5-HT3 Receptor Antagonists and ECG Effects. Pharmacotherapy Updates; 2002. Available at: 93. Warr DG, Hesketh PJ, Gralla RJ, et al. Efficacy and tolerability of http://www.clevelandclinicmeded.com/medicalpubs/pharmacy/novdec2 aprepitant for the prevention of chemotherapy-induced nausea and 002/5ht.htm. vomiting in patients with breast cancer after moderately emetogenic chemotherapy. J Clin Oncol 2005;23:2822-2830. Available at: 88. Gralla RJ, de Wit R, Herrstedt J, et al. Antiemetic efficacy of the http://www.ncbi.nlm.nih.gov/pubmed/15837996. neurokinin-1 antagonist, aprepitant, plus a 5HT3 antagonist and a corticosteroid in patients receiving or 94. Rapoport BL, Jordan K, Boice JA, et al. Aprepitant for the cyclophosphamide in addition to high-dose cisplatin: analysis of prevention of chemotherapy-induced nausea and vomiting associated combined data from two Phase III randomized clinical trials. Cancer with a broad range of moderately emetogenic chemotherapies and 2005;104:864-868. Available at: tumor types: a randomized, double-blind study. Support Care Cancer http://www.ncbi.nlm.nih.gov/pubmed/15973669. 2010;18:423-431. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19568773. 89. Hesketh PJ, Grunberg SM, Gralla RJ, et al. The oral neurokinin-1 antagonist aprepitant for the prevention of chemotherapy-induced 95. Merck & Co., Inc. . Prescribing Information. EMEND (aprepitant) nausea and vomiting: a multinational, randomized, double-blind, Capsules. 2011. Available at: placebo-controlled trial in patients receiving high-dose cisplatin--the http://www.merck.com/product/usa/pi_circulars/e/emend/emend_pi.pdf Aprepitant Protocol 052 Study Group. J Clin Oncol 2003;21:4112- . Accessed June 2011. 4119. Available at: http://www.ncbi.nlm.nih.gov/pubmed/14559886. 96. Chawla SP, Grunberg SM, Gralla RJ, et al. Establishing the dose of the oral NK1 antagonist aprepitant for the prevention of

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chemotherapy-induced nausea and vomiting. Cancer 2003;97:2290- vomiting. N Engl J Med 1981;305:905-909. Available at: 2300. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12712486. http://www.ncbi.nlm.nih.gov/pubmed/7024807.

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111. Kris MG, Gralla RJ, Clark RA, et al. Antiemetic control and 118. Passik SD, Lundberg J, Kirsh KL, et al. A pilot exploration of the prevention of side effects of anti-cancer therapy with lorazepam or antiemetic activity of olanzapine for the relief of nausea in patients diphenhydramine when used in combination with metoclopramide plus with advanced cancer and pain. J Pain Symptom Manage dexamethasone. A double-blind, randomized trial. Cancer 2002;23:526-532. Available at: 1987;60:2816-2822. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12067777. http://www.ncbi.nlm.nih.gov/pubmed/3315176. 119. Navari RM, Einhorn LH, Loehrer PJ, Sr., et al. A phase II trial of 112. Herman TS, Einhorn LH, Jones SE, et al. Superiority of nabilone olanzapine, dexamethasone, and palonosetron for the prevention of over prochlorperazine as an antiemetic in patients receiving cancer chemotherapy-induced nausea and vomiting: a Hoosier oncology chemotherapy. N Engl J Med 1979;300:1295-1297. Available at: group study. Support Care Cancer 2007;15:1285-1291. Available at: http://www.ncbi.nlm.nih.gov/pubmed/375088. http://www.ncbi.nlm.nih.gov/pubmed/17375339.

113. Steele N, Gralla RJ, Braun DW, Young CW. Double-blind 120. Navari RM, Gray SE, Kerr AC. Olanzapine versus aprepitant for comparison of the antiemetic effects of nabilone and prochlorperazine the prevention of chemotherapy-induced nausea and vomiting (CINV): on chemotherapy-induced emesis. Cancer Treat Rep 1980;64:219- A randomized phase III trial [abstract]. J Clin Oncol 2010;28(Supple 224. Available at: http://www.ncbi.nlm.nih.gov/pubmed/6250699. 15):Abstract 9020. Available at: http://meeting.ascopubs.org/cgi/content/abstract/28/15_suppl/9020. 114. Navari RM, Einhorn LH, Passik SD, et al. A phase II trial of olanzapine for the prevention of chemotherapy-induced nausea and 121. Navari RM, Gray SE, Kerr AC. Olanzapine versus aprepitant for vomiting: a Hoosier Oncology Group study. Support Care Cancer the prevention of chemotherapy-induced nausea and vomiting: a 2005;13:529-534. Available at: randomized phase III trial. J Support Oncol 2011;9:188-195. Available http://www.ncbi.nlm.nih.gov/pubmed/15700131. at: http://www.ncbi.nlm.nih.gov/pubmed/22024310.

115. Srivastava M, Brito-Dellan N, Davis MP, et al. Olanzapine as an 122. Tan L, Liu J, Liu X, et al. Clinical research of Olanzapine for antiemetic in refractory nausea and vomiting in advanced cancer. J prevention of chemotherapy-induced nausea and vomiting. J Exp Clin Pain Symptom Manage 2003;25:578-582. Available at: Cancer Res 2009;28:131. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12782438. http://www.ncbi.nlm.nih.gov/pubmed/19775450.

116. Passik SD, Navari RM, Jung S-H, et al. A phase I trial of 123. Eli Lilly and Company. Prescribing Information. ZYPREXA olanzapine (Zyprexa) for the prevention of delayed emesis in cancer (olanzapine) 2010. Available at: http://pi.lilly.com/us/zyprexa-pi.pdf. patients: a Hoosier Oncology Group study. Cancer Invest Accessed June 2011. 2004;22:383-388. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15493359. 124. Morita T, Tei Y, Shishido H, Inoue S. Olanzapine-induced delirium in a terminally ill cancer patient. J Pain Symptom Manage 117. Passik SD, Kirsh KL, Theobald DE, et al. A retrospective chart 2004;28:102-103. Available at: review of the use of olanzapine for the prevention of delayed emesis in http://www.ncbi.nlm.nih.gov/pubmed/15276190. cancer patients. J Pain Symptom Manage 2003;25:485-488. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12727048.

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NCCN Guidelines Version 2.2015 NCCN Guidelines Index Antiemesis Table of Contents Antiemesis Discussion

125. Cruz FM, de Iracema Gomes Cubero D, Taranto P, et al. 2010;39:330-336. Available at: Gabapentin for the prevention of chemotherapy- induced nausea and http://www.ncbi.nlm.nih.gov/pubmed/20022195. vomiting: a pilot study. Support Care Cancer 2012;20:601-606. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21465325. 132. Vinson DR. Diphenhydramine in the treatment of induced by prochlorperazine. J Emerg Med 2004;26:265-270. 126. National Cancer Institute. Eating Hints: Before, During, and After Available at: http://www.ncbi.nlm.nih.gov/pubmed/15028322. Cancer Treatment. 2009. Available at: http://www.cancer.gov/cancertopics/coping/eatinghints/page1. 133. Roila F, Warr D, Clark-Snow RA, et al. Delayed emesis: Accessed June 2011. moderately emetogenic chemotherapy. Support Care Cancer 2005;13:104-108. Available at: 127. Geling O, Eichler H-G. Should 5-hydroxytryptamine-3 receptor http://www.ncbi.nlm.nih.gov/pubmed/15549426. antagonists be administered beyond 24 hours after chemotherapy to prevent delayed emesis? Systematic re-evaluation of clinical evidence 134. Roscoe JA, Heckler CE, Morrow GR, et al. Prevention of delayed and drug cost implications. J Clin Oncol 2005;23:1289-1294. Available nausea: a university of Rochester cancer center community clinical at: http://www.ncbi.nlm.nih.gov/pubmed/15718327. oncology program study of patients receiving chemotherapy. J Clin Oncol 2012;30:3389-3395. Available at: 128. United States Food and Drug Administration FDA News Release: http://www.ncbi.nlm.nih.gov/pubmed/22915657. FDA Requires Boxed Warning and Risk Mitigation Strategy for Metoclopramide-Containing Drugs Agency warns against chronic use 135. Multinational Association of Supportive Care in Cancer. of these products to treat gastrointestinal disorders. 2009. Available MASCC/ESMO Antiemetic Guideline. 2011. Available at: at: http://data.memberclicks.com/site/mascc/MASCC_Guidelines_English http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/200 _2011.pdf. Accessed March 2013. 9/ucm149533.htm. Accessed June 2011. 136. Grunberg S, Clark-Snow RA, Koeller J. Chemotherapy-induced 129. Pasricha PJ, Pehlivanov N, Sugumar A, Jankovic J. Drug Insight: nausea and vomiting: contemporary approaches to optimal from disturbed motility to disordered movement--a review of the management : Proceedings from a symposium at the 2008 clinical benefits and medicolegal risks of metoclopramide. Nat Clin Multinational Association of Supportive Care in Cancer (MASCC) Pract Gastroenterol Hepatol 2006;3:138-148. Available at: Annual Meeting. Support Care Cancer 2010. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16511548. http://www.ncbi.nlm.nih.gov/pubmed/20084406.

130. Kawanishi C, Onishi H, Kato D, et al. Unexpectedly high 137. Ormrod D, Goa KL. Intranasal metoclopramide. Drugs prevalence of akathisia in cancer patients. Palliat Support Care 1999;58:315-322; discussion 323-314. Available at: 2007;5:351-354. Available at: http://www.ncbi.nlm.nih.gov/pubmed/10473023. http://www.ncbi.nlm.nih.gov/pubmed/18044412. 138. Navari RM, Nagy CK, Gray SE. The use of olanzapine versus 131. Patanwala AE, Amini R, Hays DP, Rosen P. Antiemetic therapy metoclopramide for the treatment of breakthrough chemotherapy- for nausea and vomiting in the emergency department. J Emerg Med induced nausea and vomiting (CINV) in patients receiving highly emetogenic chemotherapy [abstract]. J Clin Oncol 2012;30:Abstract

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NCCN Guidelines Version 2.2015 NCCN Guidelines Index Antiemesis Table of Contents Antiemesis Discussion

9064. Available at: prophylaxis of nausea and emesis following fractionated upper http://meeting.ascopubs.org/cgi/content/abstract/30/15_suppl/9064. abdominal radiotherapy. Cancer Invest 2001;19:763-772. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11768028. 139. Navari RM, Nagy CK, Gray SE. The use of olanzapine versus metoclopramide for the treatment of breakthrough chemotherapy- 146. Spitzer TR, Friedman CJ, Bushnell W, et al. Double-blind, induced nausea and vomiting in patients receiving highly emetogenic randomized, parallel-group study on the efficacy and safety of oral chemotherapy. Support Care Cancer 2013;21:1655-1663. Available at: granisetron and oral ondansetron in the prophylaxis of nausea and http://www.ncbi.nlm.nih.gov/pubmed/23314603. vomiting in patients receiving hyperfractionated total body irradiation. Bone Marrow Transplant 2000;26:203-210. Available at: 140. Urba S. Radiation-induced nausea and vomiting. J Natl Compr http://www.ncbi.nlm.nih.gov/pubmed/10918432. Canc Netw 2007;5:60-65. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17239327. 147. Roscoe JA, Morrow GR, Aapro MS, et al. Anticipatory nausea and vomiting. Support Care Cancer 2010. Available at: 141. Maranzano E, Feyer P, Molassiotis A, et al. Evidence-based http://www.ncbi.nlm.nih.gov/pubmed/20803345. recommendations for the use of antiemetics in radiotherapy. Radiother Oncol 2005;76:227-233. Available at: 148. Aapro MS, Molassiotis A, Olver I. Anticipatory nausea and http://www.ncbi.nlm.nih.gov/pubmed/16150504. vomiting. Support Care Cancer 2005;13:117-121. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15599779. 142. Salvo N, Doble B, Khan L, et al. Prophylaxis of radiation-induced nausea and vomiting using 5-hydroxytryptamine-3 serotonin receptor 149. Ezzo J, Vickers A, Richardson MA, et al. Acupuncture-point antagonists: a systematic review of randomized trials. Int J Radiat stimulation for chemotherapy-induced nausea and vomiting. J Clin Oncol Biol Phys 2010. Available at: Oncol 2005;23:7188-7198. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21075553. http://www.ncbi.nlm.nih.gov/pubmed/16192603.

143. Franzen L, Nyman J, Hagberg H, et al. A randomised placebo 150. Morrow GR, Morrell C. Behavioral treatment for the anticipatory controlled study with ondansetron in patients undergoing fractionated nausea and vomiting induced by cancer chemotherapy. N Engl J Med radiotherapy. Ann Oncol 1996;7:587-592. Available at: 1982;307:1476-1480. Available at: http://www.ncbi.nlm.nih.gov/pubmed/8879372. http://www.ncbi.nlm.nih.gov/pubmed/6128673.

144. Wong RK, Paul N, Ding K, et al. 5-hydroxytryptamine-3 receptor 151. Redd WH, Andrykowski MA. Behavioral intervention in cancer antagonist with or without short-course dexamethasone in the treatment: controlling aversion reactions to chemotherapy. J Consult prophylaxis of radiation induced emesis: a placebo-controlled Clin Psychol 1982;50:1018-1029. Available at: randomized trial of the National Cancer Institute of Canada Clinical http://www.ncbi.nlm.nih.gov/pubmed/7174969. Trials Group (SC19). J Clin Oncol 2006;24:3458-3464. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16849762. 152. Ezzo J, Streitberger K, Schneider A. Cochrane systematic reviews examine P6 acupuncture-point stimulation for nausea and 145. Lanciano R, Sherman DM, Michalski J, et al. The efficacy and vomiting. J Altern Complement Med 2006;12:489-495. Available at: safety of once-daily Kytril (granisetron hydrochloride) tablets in the http://www.ncbi.nlm.nih.gov/pubmed/16813514.

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NCCN Guidelines Version 2.2015 NCCN Guidelines Index Antiemesis Table of Contents Antiemesis Discussion

153. Figueroa-Moseley C, Jean-Pierre P, Roscoe JA, et al. Behavioral Palliat Care 2008;2:28-34. Available at: interventions in treating anticipatory nausea and vomiting. J Natl http://www.ncbi.nlm.nih.gov/pubmed/18685391. Compr Canc Netw 2007;5:44-50. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17239325. 160. Einhorn LH, Rapoport B, Koeller J, et al. Antiemetic therapy for multiple-day chemotherapy and high-dose chemotherapy with stem 154. Molassiotis A, Yung HP, Yam BM, et al. The effectiveness of cell transplant: review and consensus statement. Support Care progressive muscle relaxation training in managing chemotherapy- Cancer 2005;13:112-116. Available at: induced nausea and vomiting in Chinese breast cancer patients: a http://www.ncbi.nlm.nih.gov/pubmed/15480812. randomised controlled trial. Support Care Cancer 2002;10:237-246. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11904789. 161. Navari RM. Prevention of emesis from multiple-day and high- dose chemotherapy regimens. J Natl Compr Canc Netw 2007;5:51-59. 155. Razavi D, Delvaux N, Farvacques C, et al. Prevention of Available at: http://www.ncbi.nlm.nih.gov/pubmed/17239326. adjustment disorders and anticipatory nausea secondary to adjuvant chemotherapy: a double-blind, placebo-controlled study assessing the 162. Herrstedt J, Sigsgaard TC, Nielsen HA, et al. Randomized, usefulness of alprazolam. J Clin Oncol 1993;11:1384-1390. Available double-blind trial comparing the antiemetic effect of tropisetron plus at: http://www.ncbi.nlm.nih.gov/pubmed/8315437. with tropisetron plus placebo in patients receiving multiple cycles of multiple-day cisplatin-based chemotherapy. Support 156. Malik IA, Khan WA, Qazilbash M, et al. Clinical efficacy of Care Cancer 2007;15:417-426. Available at: lorazepam in prophylaxis of anticipatory, acute, and delayed nausea http://www.ncbi.nlm.nih.gov/pubmed/17093916. and vomiting induced by high doses of cisplatin. A prospective randomized trial. Am J Clin Oncol 1995;18:170-175. Available at: 163. Mier JW, Vachino G, Klempner MS, et al. Inhibition of interleukin- http://www.ncbi.nlm.nih.gov/pubmed/7900711. 2-induced tumor necrosis factor release by dexamethasone: prevention of an acquired neutrophil chemotaxis defect and differential 157. Pfizer. Prescribing Information. XANAX® alprazolam tablets. suppression of interleukin-2-associated side effects. 2011. Available at: 1990;76:1933-1940. Available at: http://labeling.pfizer.com/ShowLabeling.aspx?id=547. Accessed June http://www.ncbi.nlm.nih.gov/pubmed/2242421. 2011. 164. Musso M, Scalone R, Bonanno V, et al. Palonosetron (Aloxi) and 158. de Wit R, Herrstedt J, Rapoport B, et al. The oral NK(1) dexamethasone for the prevention of acute and delayed nausea and antagonist, aprepitant, given with standard antiemetics provides vomiting in patients receiving multiple-day chemotherapy. Support protection against nausea and vomiting over multiple cycles of Care Cancer 2009;17:205-209. Available at: cisplatin-based chemotherapy: a combined analysis of two http://www.ncbi.nlm.nih.gov/pubmed/18839220. randomised, placebo-controlled phase III clinical trials. Eur J Cancer 2004;40:403-410. Available at: 165. Celio L, Denaro A, Canova S, et al. Clinical update on http://www.ncbi.nlm.nih.gov/pubmed/14746859. palonosetron in the management of chemotherapy-induced nausea and vomiting. Tumori 2008;94:447-452. Available at: 159. Ellebaek E, Herrstedt J. Optimizing antiemetic therapy in http://www.ncbi.nlm.nih.gov/pubmed/18822676. multiple-day and multiple cycles of chemotherapy. Curr Opin Support

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NCCN Guidelines Version 2.2015 NCCN Guidelines Index Antiemesis Table of Contents Antiemesis Discussion

166. Eisenberg P, MacKintosh FR, Ritch P, et al. Efficacy, safety and pharmacokinetics of palonosetron in patients receiving highly emetogenic cisplatin-based chemotherapy: a dose-ranging clinical study. Ann Oncol 2004;15:330-337. Available at: http://www.ncbi.nlm.nih.gov/pubmed/14760130.

167. Einhorn LH, Brames MJ, Dreicer R, et al. Palonosetron plus dexamethasone for prevention of chemotherapy-induced nausea and vomiting in patients receiving multiple-day cisplatin chemotherapy for germ cell cancer. Support Care Cancer 2007;15:1293-1300. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17436025.

168. Giralt SA, Mangan KF, Maziarz RT, et al. Three palonosetron regimens to prevent CINV in myeloma patients receiving multiple-day high-dose melphalan and hematopoietic stem cell transplantation. Ann Oncol 2010. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20935058.

169. Jordan K, Kinitz I, Voigt W, et al. Safety and efficacy of a triple antiemetic combination with the NK-1 antagonist aprepitant in highly and moderately emetogenic multiple-day chemotherapy. Eur J Cancer 2009;45:1184-1187. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19135359.

170. Olver IN, Grimison P, Chatfield M, et al. Results of a 7-day aprepitant schedule for the prevention of nausea and vomiting in 5-day cisplatin-based germ cell tumor chemotherapy. Support Care Cancer 2013;21:1561-1568. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23274926.

171. Albany C, Brames MJ, Fausel C, et al. Randomized, double- blind, placebo-controlled, phase III cross-over study evaluating the oral neurokinin-1 antagonist aprepitant in combination with a 5HT3 receptor antagonist and dexamethasone in patients with germ cell tumors receiving 5-day cisplatin combination chemotherapy regimens: a hoosier oncology group study. J Clin Oncol 2012;30:3998-4003. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22915652.

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