PERUGIA INTERNATIONAL CANCER CONFERENCE VII MULTINATIONAL ASSOCIATION FOR SUPPORTIVE CARE IN CANCER

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1 June 2004 PERUGIA INTERNATIONAL CANCER CONFERENCE VII MULTINATIONAL ASSOCIATION FOR SUPPORTIVE CARE IN CANCER CONSENSUS CONFERENCE ON ANTIEMETIC THERAPY PERUGIA, March 29-31, 2004 DELAYED EMESIS WORKING PARTY Paul J Hesketh; Ian Olver; Enzo Ballatori; Susanne Börjeson; Jim Koeller; Mark Kris; Fausto Roila David Warr; Rebecca A. Clark; Maurizio Tonato ; Richard J Gralla, Lawrence H. Einhorn; Jorn Herrstedt PRESENTED BY M. AAPRO

2 June 2004 ANTIEMETIC GUIDELINE CONSENSUS - A few comments on this guideline set - This set of guideline slides is based on the first edition of the guideline process from the Perugia meeting. Those slides released by MASCC are identified by the MASCC logo Personnal slides do not have the logo These findings reflect the reports from ASCO 2004, not of MASCC These meetings may have the greatest effect on guidelines concerning the use of Aprepitant or Palonosetron

3 IS DURATION OF ACTION A KEY DETERMINANT? PALONOSETRON: 40 hours T1/2

4 Is acute control the key against delayed CINV? Patients Responding (%) * No response to acute antiemetic therapy Responders to acute antiemetic therapy 0 Delayed Control *P<.001 vs day 0. Goedhals et al. Ann Oncol.1998;9(6):

5 SETRONS and DELAYED EMESIS MEC Acute: dex+ond Dealyed: oral ond or placebo KAIZER,NCIC,ASCO 92, JCO No delayed vomiting (%) Not published placebo Placebo Ondan 0

6 Dexamethasone Summary Tablets <1.5mg only 1.5 mg (max) 2.0mg or > Central America Czech Republic Denmark France Hong Kong Hungary Italy South Africa Mexico Turkey Spain Korea others Sweden Holland Finland Belgium Germany United Kingdom Iceland Austria Australia Switzerland Israel New Zealand Canada Status

7 June 2004 PERUGIA 2004 ANTIEMETIC GUIDELINES - Committees and their Areas (1/2) - I. Emetic classification of antineoplastic agents II. Acute emesis: Highly emetic chemotherapy III. Delayed emesis: Highly emetic chemotherapy IV. Acute emesis: Moderately emetic chemotherapy V. Delayed emesis: Moderately emetic chemotherapy

8 June 2004 PERUGIA 2004 ANTIEMETIC GUIDELINES - Committees and their Areas (2/2) - VI. VII. Emesis induced by minimal or low emetic risk chemotherapy Additional Issues: Refractory emesis, rescue antiemetic therapy,multiple-day chemotherapy, high-dose chemotherapy VIII. Anticipatory emesis IX. Radiotherapy-induced emesis, Antiemetics in children receiving chemotherapy X. Future Considerations: Research Directions, Study Design, Economic Considerations

9 June 2004 COMMITTEE III: Guideline for the Prevention of Delayed Nausea and Vomiting Following Chemotherapy of High Emetic Risk: In patients receiving cisplatin treated with a combination of aprepitant, a 5-HT 3 receptor antagonist and dexamethasone to prevent acute vomiting and nausea, the combination of dexamethasone and aprepitant is suggested to prevent delayed emesis, on the basis of its superiority to dexamethasone alone. MASCC Level of Consensus: Moderate MASCC Level of Confidence: High ASCO Level of Evidence: II ASCO Grade of Recommendation: A

10 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 such as: AC, EC, FAC, and FEC. A = doxorubicin, E = epirubicin, C = cyclophosphamide, F = 5-FU.

11 Effect of aprepitant on the prevention of nausea and vomiting after one cycle of moderately emetogenic chemotherapy: A randomized double-blind blind trial in 866 patients David Warr, Peter Eisenberg, Paul Hesketh, Richard J. Gralla, Hyman Muss, Harry Raftopolous, Munir Gabriel, Anthony Rodgers, Carolyn Hustad, Franck Skobieranda

12 Study Design Key Inclusion Criterion IV cyclophosphamide + anthracycline- based chemotherapy in patients with breast cancer Key Exclusion Criterion Concomitant/recent use of drugs that are inducers of CYP3A4 (aprepitant is metabolized by CYP3A4)

13 Study Schema Group Day 1 Days 2-3 Ond Dex Aprepitant Ond Aprepitant Standard 8 mg bid 20 mg Placebo 8 mg bid Placebo Aprepitant 8 mg bid 12 mg 125 mg Placebo 80 mg Ond = ondansetron p.o. Dex = dexamethasone p.o.

14 Complete Response h post AC Standard Aprepitant Difference = 8.3% P=0.015

15 Time To First Emesis Percent of Patients 100% 90% 80% 70% 60% Aprepitant Standard 50% 40% Hours Since First Chemotherapy Administration

16 June 2004 COMMITTEE V (1/2): Guideline for prevention of delayed nausea and vomiting in patients receiving moderately emetic chemotherapy: Patients who receive MEC known to be associated with a significant incidence of delayed nausea and vomiting should receive antiemetic prophylaxis for delayed emesis. MASCC level of confidence: high MASCC level of consensus: high ASCO level of evidence: I ASCO grade of recommendation: A

17 June 2004 COMMITTEE V (2/2): Guideline for prevention of delayed nausea and vomiting in patients receiving moderately emetic chemotherapy: Oral dexamethasone is the preferred treatment MASCC level of confidence: high MASCC level of consensus: high ASCO level of evidence: II ASCO grade of recommendation: A A 5-HT 3 receptor antagonist may be used as an alternative. MASCC level of confidence: moderate MASCC level of consensus: moderate ASCO level of evidence: II ASCO grade of recommendation: B

18 Aapro, Annals of Oncology, 2003 SAKK: acute and delayed emesis control in clinical reality 267 patients oral antiemetics ACUTE: granisetron 2 mg + Dex 8 mg DELAYED PHASE: ALL: Dex 4 mg x4 d with randomise : mcp 3x20 mg or kytril 2x1 mg ( double-blind; double-dummy ) ACUTE DELAYED MCP GRANISETRON

19 CONCLUSIONS Delayed vomiting ( nausea) ( Pater, Ann. Oncol. 8:181-5, 1997) remains a somewhat unsolved issue Excellent acute control remains a determinant of delayed phase outcome