chemotherapy-induced acute emesis cisplatin with a 5-ht3-or nk 1 ra patients with no emesis (%) time

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  • JØRN HERRSTEDT, M.D. COPENHAGEN UNIVERSITY HOSPITAL

    HERLEV, DENMARK

    CHEMOTHERAPY-INDUCED ACUTE EMESIS

    SCIENTIFIC SESSION: THE PERUGIA CONSENSUS ON NAUSEA AND VOMITING

  • June 2004

    PERUGIA 2004 ANTIEMETIC GUIDELINES - Committees and their Areas

    I. Emetic classification of antineoplastic agents

    II. Acute emesis: Highly emetic chemotherapy

    IV. Acute emesis: Moderately emetic chemotherapy

    VI. Emesis induced by minimal or low emetic risk chemotherapy

  • June 2004

    PARTICIPANTS IN THE PERUGIA ANTIEMETIC COMMITEES I, II, IV and VI

    Enzo Ballatori, PhD Sussanne Borjeson, RN, PhD Rebecca Clark-Snow, RN, BSN, OCN Albano Del Favero, MD Lawrence Einhorn, MD Richard Gralla, MD Steven Grunberg, MD Jørn Herrstedt, MD Paul Hesketh, MD

    Jim Koeller, RPh, MS

    Mark Kris, MD

    David Osoba, MD

    Bernardo Rapoport, MD

    Cynthia Rittenberg, RN, MN, AOCN

    Fausto Roila, MD

    Maurizio Tonato, MD

    David Warr, MD

  • DEFINITION OF

    ACUTE EMESIS

  • June 2004

    Time course of emesis following cisplatin with a 5-HT3- or NK1 RA Patients with no emesis (%)

    Time (h) since initiation of cisplatin

    0 8 24 40 60 80 100 120 0

    20

    40

    60

    80

    100 GRA + DEX + PLA 5 days Aprepitant + GRA + DEX 6 days Aprepitant + DEX + PLA 5 days Aprepitant + DEX + PLA

    Hesketh PJ et al. Eur J Cancer 2003;39:1074-80.

  • DEFINITION OF

    EMETIC RISK

  • June 2004

    PERUGIA 2004 ANTIEMETIC GUIDELINES

    ANTIEMETIC TREATMENT GUIDELINES - Committee I (1/5): The Four Emetic Risk Groups -

    Fewer than 10% at risk

    Risk in 10% to 30% of patients

    Risk in 30% to 90% of patients

    Risk in nearly all patients (> 90%)

    MINIMAL

    LOW

    MODERATE

    HIGH

    Multinational Association of Supportive Care in Cancer June 2004

  • June 2004

    COMMITTEE II and IV - Principles of Care for Acute Highly and Moderately Emetic Settings -

    UNANIMOUS CONSENSUS: CATEGORY I EVIDENCE

    - Use the lowest tested fully effective dose - No schedule is better than a single dose given

    before chemotherapy - The antiemetic efficacy and adverse effects of these

    agents are comparable in controlled trials - Intravenous and oral formulations are equally effective

    and safe* - Always give dexamethasone with a 5-HT3 antagonist

    before chemotherapy

    * Palonosetron has only been investigated as an IV formulation.

    Multinational Association of Supportive Care in Cancer June 2004

  • June 2004

    ANTIEMETIC TREATMENT GUIDELINES Committee I: Emetic Risk Groups – High Risk

    Single IV agents

    Single oral agents

    Cisplatin Mechlorethamine Streptozotocin Cyclophosphamide > 1500 mg/m2 Carmustine Dacarbazine

    Hexamethylmelamine Procarbazine

  • June 2004

    COMMITTEE II:

    Guideline for the Prevention of Acute Nausea and Vomiting Following Chemotherapy of High Emetic Risk:

    To prevent acute vomiting and nausea following chemotherapy of high emetic risk, a three-drug regimen including single doses of a 5-HT3 antagonist, dexamethasone, and aprepitant given before chemotherapy is recommended.

    MASCC Level of Consensus: High MASCC Level of Confidence: High

    ASCO Level of Evidence: I ASCO Grade of Recommendation: A

    June 2004Multinational Association of Supportive Care in Cancer

  • June 2004

    ANTIEMETIC TREATMENT GUIDELINES - Committee I: Emetic Risk Groups – Moderate Risk

    Single IV agents Oxaliplatin Cytarabine > 1 gm/m2 Carboplatin Ifosfamide Cyclophosphamide < 1500 mg/m2 Doxorubicin Daunorubicin Epirubicin Idarubicin Irinotecan

    Single oral agents Cyclophosphamide Etoposide Temozolomide Vinorelbine Imatinib

  • June 2004

    COMMITTEE IV (1/3):

    Guideline for prevention of acute emesis in moderately emetic chemotherapy (MEC):

    A 5-HT3 receptor antagonist plus dexamethasone is recommended for prophylaxis of acute nausea and vomiting in the first course of MEC.

    MASCC level of confidence: High MASCC level of consensus: High

    ASCO level of evidence: I ASCO grade of recommendation: A

    Multinational Association of Supportive Care in Cancer June 2004

  • June 2004

    Palonosetron Phase III studies Acute phase

    NS67%OndansetronHigh

    Palo superior0%OndansetronModerate

    NS4-6% DolasetronModerate

    CRDexComparatorEmetic risk group

  • June 2004

    COMMITTEE IV (2/3):

    Guideline for prevention of acute emesis in moderately emetic chemotherapy:

    There are no clinically relevant differences in the effectiveness of the 5- HT3 receptor antagonists in the prophylaxis of acute nausea and vomiting when given according to guidelines in the first cycle of MEC*.

    MASCC level of confidence: High MASCC level of consensus: High

    ASCO level of evidence: I ASCO grade of recommendation: A

    * Participants felt that the comparative data with palonosetron were interesting, but indicated that studies with this agent which follow guidelines (given with dexamethasone) are needed to change this guideline.

    Multinational Association of Supportive Care in Cancer June 2004

  • June 2004

    ANTIEMETIC TREATMENT GUIDELINES Committee I: Emetic Risk Groups – Low risk

    Single IV agents Paclitaxel Docetaxel Mitoxantrone Topotecan Etoposide Pemetrexed Methotrexate Mitomycin Gemcitabine Cytarabine < 100 mg/m2 5-Fluorouracil Bortezomib Cetuximab Trastuzumab

    Single oral agents Capecetabine

  • June 2004

    COMMITTEE VI (1/2):

    Guideline for prevention of acute nausea and vomiting in patients receiving low risk emetic agents*:

    A single agent (such as a low dose of a corticosteroid) is suggested for patients receiving agents of low emetic risk.

    MASCC: Level of confidence: No confidence possible. MASCC: Level of consensus: moderate

    ASCO level of evidence: III, IV ASCO grade of recommendation: D

    * While unusual at this emetic level, if a patient experiences emesis after guideline recommended therapy, it is advised that with subsequent treatment the regimen for the next higher emetic level should be given.

    Multinational Association of Supportive Care in Cancer June 2004

  • June 2004

    ANTIEMETIC TREATMENT GUIDELINES Committee I: Emetic Risk Groups – Minimal Risk

    Bleomycin Busulfan 2-Chlorodeoxyadenosine Fludarabine Vinblastine Vincristine Vinorelbine Bevacizumab

    Chlorambucil Hydroxyurea L-Phenylalanine mustard 6-Thioguanine Methotrexate Gefitinib

    Single oral agents

    Single IV agents

  • June 2004

    COMMITTEE VI (2/2):

    Guideline for prevention of acute nausea and vomiting in patients receiving minimal risk antineoplastic agents*:

    No antiemetic should be routinely administered before chemotherapy in patients without a history of nausea and vomiting.

    MASCC level of confidence: no confidence possible MASCC level of consensus: high

    ASCO level of evidence: V and expert consensus ASCO grade of recommendation: D

    * While unusual at this emetic level, if a patient experiences emesis after guideline recommended therapy, it is advised that with subsequent treatment the regimen for the next higher emetic level should be given.

    Multinational Association of Supportive Care in Cancer June 2004

  • June 2004

    RECOMMENDED DOSES

    OF ANTIEMETICS

  • June 2004

    Recommended Doses of Serotonin Receptor (5-HT3) Antagonists for Acute Emesis

    0.25 mgIVPalonosetron 5 mgOral 5 mgIVTropisetron

    100 mgOral 100 mg or 1.8 mg / KgIVDolasetron

    2 mg (or 1 mg**)Oral 1 mg or 0.01 mg / KgIVGranisetron

    16 mg*Oral 8 mg or 0.15 mg / KgIVOndansetron

    DOSEROUTEAGENT

    * Randomized studies have tested the 8 mg twice daily schedule ** The 1 mg dose preferred by some panelists: small randomized study in MEC, Phase II study in HEC

    Multinational Association of Supportive Care in Cancer June 2004

  • June 2004

    Recommended Dexamethasone and Aprepitant Dosing

    - Acute Emesis

    - Delayed Emesis

    - Acute Emesis

    - Delayed Emesis

    - Acute Emesis

    80 mg orally, once for 2 days- Delayed Emesis

    125 mg orally, once- Acute Emesis

    Dose and ScheduleAPREPITANT

    4 - 8 mg onceLow Risk

    8 mg daily for 2 - 3 days (many panelists give the dose as 4 mg bid)

    8 mg once Moderate Risk

    8 mg bid for 3 - 4 days

    20 mg once High Risk

    Dose and ScheduleDEXAMETHASONE

    Multinational Association of Supportive Care in Cancer June 2004

  • June 2004

    MULTIPLE CYCLES

  • June 2004

    Addressing “AC”* as a Separate Group Groups II - V

    Although not part of the official recommendations for acute emesis in MEC, the panel agreed that it should be recognized that women receiving a combination of anthracycline plus cyclophosphamide represents a situation with a particularly great risk of nausea and vomiting. Additionally, it appears that the risk of nausea and vomiting increases during multiple cycles.

    * AC = Anthracycline + Cyclophosphamide, includes regimens s