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, PhDSussanne Borjeson, RN, PhDRebecca Clark-Snow, RN, BSN, OCNAlbano Del Favero, MDLawrence Einhorn, MDRichard Gralla, MDSteven Grunberg, MDJørn Herrstedt, MDPaul 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
June 2004
Time course of emesis following cisplatin with a 5-HT3- or NK1 RAPatients with no emesis (%)
Time (h) since initiation of cisplatin
0 8 24 40 60 80 100 1200
20
40
60
80
100 GRA + DEX + PLA5 days Aprepitant + GRA + DEX6 days Aprepitant + DEX + PLA5 days Aprepitant + DEX + PLA
Hesketh PJ et al. Eur J Cancer 2003;39:1074-80.
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 givenbefore chemotherapy
- The antiemetic efficacy and adverse effects of theseagents are comparable in controlled trials
- Intravenous and oral formulations are equally effectiveand safe*
- Always give dexamethasone with a 5-HT3 antagonistbefore chemotherapy
* Palonosetron has only been investigated as an IV formulation.
Multinational Association of Supportive Care in Cancer June 2004
June 2004
ANTIEMETIC TREATMENT GUIDELINESCommittee I: Emetic Risk Groups – High Risk
Single IV agents
Single oral agents
CisplatinMechlorethamineStreptozotocinCyclophosphamide > 1500 mg/m2CarmustineDacarbazine
HexamethylmelamineProcarbazine
June 2004
COMMITTEE II:
Guideline for the Prevention of Acute Nausea and VomitingFollowing Chemotherapy of High Emetic Risk:
To prevent acute vomiting and nausea following chemotherapyof high emetic risk, a three-drug regimen including single dosesof a 5-HT3 antagonist, dexamethasone, and aprepitant givenbefore chemotherapy is recommended.
MASCC Level of Consensus: HighMASCC Level of Confidence: High
ASCO Level of Evidence: IASCO 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 OxaliplatinCytarabine > 1 gm/m2CarboplatinIfosfamideCyclophosphamide < 1500 mg/m2DoxorubicinDaunorubicinEpirubicinIdarubicinIrinotecan
Single oral agents CyclophosphamideEtoposideTemozolomideVinorelbineImatinib
June 2004
COMMITTEE IV (1/3):
Guideline for prevention of acute emesis in moderately emetic chemotherapy (MEC):
A 5-HT3 receptor antagonist plus dexamethasoneis recommended for prophylaxis of acute nauseaand vomiting in the first course of MEC.
MASCC level of confidence: HighMASCC level of consensus: High
ASCO level of evidence: IASCO 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: HighMASCC level of consensus: High
ASCO level of evidence: IASCO 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 GUIDELINESCommittee I: Emetic Risk Groups – Low risk
Single IV agents PaclitaxelDocetaxelMitoxantroneTopotecanEtoposidePemetrexedMethotrexateMitomycinGemcitabineCytarabine < 100 mg/m25-FluorouracilBortezomibCetuximabTrastuzumab
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, IVASCO 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 GUIDELINESCommittee I: Emetic Risk Groups – Minimal Risk
BleomycinBusulfan2-ChlorodeoxyadenosineFludarabineVinblastineVincristineVinorelbineBevacizumab
ChlorambucilHydroxyureaL-Phenylalanine mustard6-ThioguanineMethotrexateGefitinib
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 beforechemotherapy in patients without a history of nauseaand vomiting.
MASCC level of confidence: no confidence possibleMASCC level of consensus: high
ASCO level of evidence: V and expert consensusASCO 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 Serotonin Receptor(5-HT3) Antagonists for Acute Emesis
0.25 mgIVPalonosetron5 mgOral5 mgIVTropisetron
100 mgOral100 mg or 1.8 mg / KgIVDolasetron
2 mg (or 1 mg**)Oral1 mg or 0.01 mg / KgIVGranisetron
16 mg*Oral8 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 onceModerate Risk
8 mg bid for 3 - 4 days
20 mg onceHigh Risk
Dose and ScheduleDEXAMETHASONE
Multinational Association of Supportive Care in Cancer June 2004
June 2004
Addressing “AC”* as a Separate GroupGroups 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 such as: AC, EC, FAC,and FEC. A = doxorubicin, E = epirubicin, C = cyclophosphamide, F = 5-FU.
Multinational Association of Supportive Care in Cancer June 2004
June 2004
0
20
40
60
80
100
1. Cyc
le3.
Cycle
5. Cyc
le7.
Cycle
9. Cyc
le
Ondansetronplusmetopimazine
Ondansetronplusmetopimazineplusprednisolone
Cumulative complete protection rates in patients receivingCMF/CEF and antiemetic prophylaxis with ondansetron (OND)
prednisolone plus metopimazine (MPZ) or OND plus MPZ (n=220, 1462 courses of chemotherapy)
P = 0.0014
Sigsgaard et al. J Clin Oncol 2001;2091-7.
June 2004
Ongoing process to address emerging evidence in the future:
• Committees are permanent• Each chair queries the committee every 6 months regarding
whether there is new information which may affect the guideline• A steering committee queries the chairs for these suggestions• If evidence appears compelling, all group members are notified
for their opinions• If consensus is achieved, the Web-Guideline document
(MASCC) is updated. All participating Societies are notified.• Future print publications will have to be addressed – this should
be done in a coordinated way among the Societies
Keeping the Guidelines Accurate, Up-to-Date, and Valid -Keeping the Guidelines Accurate, Up-to-Date, and Valid -
PERUGIA 2004 ANTIEMETIC GUIDELINES- Process for the future:
PERUGIA 2004 ANTIEMETIC GUIDELINES- Process for the future:
Multinational Association of Supportive Care in Cancer June 2004
June 2004
Is there new information which may affect the guideline on acute nausea and vomiting?
• Does the addition of aprepitant improve the effect ofrecommended antiemetic therapy in patients receivingMEC? A-27
• Will randomized comparisons of palonosetron plus dexamethasone (+/- aprepitant) versus other 5-HT3receptor antagonists plus dexamethasone (+/- aprepitant) affect the guideline?