1. MASCC/ESMO ANTIEMETIC GUIDELINE 2013 Multinational Association of Supportive Care in Cancer Organizing and Overall Meeting Chairs: Richard J. Gralla, MD Fausto Roila, MD Maurizio Tonato, MD Jørn Herrstedt, MD © Multinational Association of Supportive Care in Cancer TM All rights reserved worldwide.

2. These slides are provided to all by the Multinational Association of Supportive Care in Cancer and can be used freely provided no changes are made and the MASCC logo and date of the information are retained. For questions please contact: Prof. Alex Molassiotis- alex.molasiotis@polyu.edu.hkalex.molasiotis@polyu.edu.hk Chair, MASCC Antiemetic Study Group

3. This set of guideline slides represents the latest edition of the guideline process. This set of panels has been endorsed by the MASCC antiemetic guideline committee. The guidelines are based on the Perugia Consensus Conference on Antiemetic Therapy June 2009. Latest update January 2013. - A few comments on this guideline set - ANTIEMETIC GUIDELINES: MASCC/ESMO - Consensus - - A few comments on this guideline set -

4. ANTIEMETIC GUIDELINES: MASCC/ESMO PARTICIPANTS IN THE PERUGIA ANTIEMETIC GUIDELINE PROCESS Matti Aapro, MD Enzo Ballatori, PhD Emilio Bria, MD Rebecca Clark-Snow, RN, BSN, OCN Lawrence Einhorn, MD Birgitte Espersen, RN Petra Feyer, MD Richard Gralla, MD Steven Grunberg, MD Jørn Herrstedt, MD Paul Hesketh, MD Karin Jordan, MD Mark Kris, MD Ernesto Maranzano, MD Alexander Molassiotis, RN, PhD Gary Morrow, PhD Ian Olver, MD, PhD Bernardo Rapoport, MD Cynthia Rittenberg, RN, MN, AOCN Fausto Roila, MD Mitsue Saito, MD Maurizio Tonato, MD David Warr, MD

5. Asia Africa Australia/Oceania Europe North America Japan South Africa Australia Denmark Germany France Italy Switzerland United Kingdom Canada United States of America ANTIEMETIC GUIDELINES: MASCC/ESMO CONTINENTS AND COUNTRIES OF PARTICIPANTS IN ANTIEMETIC GUIDELINE PROCESS

6. 5HT3DEXAPR 5HT3DEXAPR PALODEX + + ++ + 5HT 3 = serotonin receptor antagonist DEX = DEXAMETHASONE APR = APREPITANT; FOS= FOSAPREPITANT PALO = PALONOSETRON SUMMARY ACUTE NAUSEA AND VOMITING EMETIC RISK GROUPANTIEMETICS High Anthracycline + Cyclophosphamide (AC) Moderate (other than AC) Low Minimal No routine prophylaxis 5HT 3 DEX APR or FOS 5HT 3 DEXAPR or FOS PALODEX * NOTE: If the NK1 receptor antagonist is not available for AC chemotherapy, palonosetron is the preferred 5-HT 3 receptor antagonist. The Antiemetic Subcommittee of The Multinational Association of Supportive Care in Cancer. - Ann Oncol 2010; www.mascc.org. 5HT 3 DRA DRA = dopamine receptor antagonist ++ OR + + +

7. 5HT3DEXAPR 5HT3DEXAPR PALODEX + + ++ + DEX = DEXAMETHASONEAPR= APREPITANT SUMMARY DELAYED NAUSEA AND VOMITING EMETIC RISK GROUPANTIEMETICS High+ Anthracycline + Cyclophosphamide (AC) Moderate (other than AC) LowNo routine prophylaxis MinimalNo routine prophylaxis DEX*APR* APR or none** DEX The Antiemetic Subcommittee of The Multinational Association of Supportive Care in Cancer. Ann Oncol 2010; www.mascc.orgwww.mascc.org * DEX only, if FOSAPREPITANT used on Day 1 ** If FOSAPREPITANT used on Day 1

8. ANTIEMETIC GUIDELINES: MASCC/ESMO The Process 1) Each committee worked on its area of concentration prior to the Perugia Meeting. At Perugia, each committee chair presented the findings of that committee to the entire group, and included the suggested rating of the level of evidence / confidence of the guideline. 2) Group discussion and consensus voting then followed each presentation. What were the criteria for consensus? Degree of consensus required: 67% or greater agreement among the panelists was required to change a guideline. Basis of evidence to change an existing guideline: Compelling evidence was required based on well-conducted trials, generally with a comparator felt to be consistent with guidelines and representing best practice. Generally at least a 10% difference was considered to be the minimum degree of benefit sufficient for change.

9. 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 ANTIEMETIC GUIDELINES: MASCC/ESMO Committees and their Areas (1/2)

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

11. 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. ANTIEMETIC GUIDELINES: MASCC/ESMO Process for the future: Keeping the Guidelines Accurate, Up-to-Date, and Valid

12. ANTIEMETIC GUIDELINES: MASCC/ESMO Committee I (1/5): The Four Emetic Risk Groups HIGH Risk in nearly all patients (> 90%) MODERATERisk in 30% to 90% of patients LOWRisk in 10% to 30% of patients MINIMALFewer than 10% at risk

13. Committee I (2/5): Emetic Risk Groups – Single IV Agents HIGH Cisplatin Mechlorethamine Streptozocin Cyclophosphamide > 1500 mg/m2 Carmustine Dacarbazine MODERATE Oxaliplatin Cytarabine > 1000 mg/m2 Carboplatin Ifosfamide Cyclophosphamide < 1500 mg/m2 Azacitidine Alemtuzumab Doxorubicin Daunorubicin Epirubicin Idarubicin Irinotecan Bendamustine Clofarabine ANTIEMETIC GUIDELINES: MASCC/ESMO

14. Committee I (3/5): Emetic Risk Groups – Single IV Agents Low Paclitaxel Docetaxel Mitoxantrone Topotecan Etoposide Pemetrexed Methotrexate Doxorubicin HCL liposome injection Temsirolimus Ixabepilone Mitomycin Gemcitabine Cytarabine < 1000 mg/m2 5-Fluorouracil Bortezomib Cetuximab Trastuzumab Catumaxumab Panitumumab ANTIEMETIC GUIDELINES: MASCC/ESMO

15. MINIMAL Bleomycin Busulfan Cladribine Fludarabine Vinblastine Vincristine Vinorelbine Bevacizumab 2-Chlorodeoxyadenosine ANTIEMETIC GUIDELINES: MASCC/ESMO Committee I (4/5): Emetic Risk Groups – Single IV Agents

16. Committee I (5/5): Emetic Risk Groups – Single Oral Agents HIGH Hexamethylmelamine Procarbazine MODERATE Cyclophosphamide Temozolomide Vinorelbine Imatinib LOW Capecitabine Tegafur Uracil Etoposide Sunitinib Fludarabine Everolimus Lapatinib Lenalidomide Thalidomide MINIMAL Chlorambucil Hydroxyurea Melphalan Methotrexate 6-Thioguanine Gefitinib Sorafenib Erlotinib L-Phenylalanine mustard ANTIEMETIC GUIDELINES: MASCC/ESMO

17. Guideline for the Prevention of Acute Nausea and Vomiting Following Chemotherapy of High Emetic Risk: To prevent acute nausea and vomiting following chemotherapy of high emetic risk, a three-drug regimen including single doses of a 5-HT 3 receptor antagonist, dexamethasone, and aprepitant (or fosaprepitant) given before chemotherapy is recommended. Level of confidence : High Level of consensus: High ANTIEMETIC GUIDELINES: MASCC/ESMO COMMITTEE II:

18. 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 (or fosaprepitant*), a 5-HT 3 receptor antagonist and dexamethasone to prevent acute nausea and vomiting, the combination of dexamethasone and aprepitant* is suggested to prevent delayed emesis, on the basis of its superiority to dexamethasone alone. *However, if fosaprepitant is used in Day 1, only dexamethasone is required at days 2 - 4 post-chemotherapy Level of confidence : High Level of consensus: Moderate ANTIEMETIC GUIDELINES: MASCC/ESMO COMMITTEE III:

19. Guideline for the Prevention of Acute Nausea and Vomiting Following Chemotherapy of Moderate Emetic Risk: Women receiving a combination of anthracycline plus cyclophosphamide represent a situation with a particularly great risk of nausea and vomiting. To prevent acute nausea and vomiting, a three-drug regimen including single doses of a 5-HT 3 receptor antagonist, dexamethasone, and aprepitant (or fosaprepitant), given before chemotherapy is recommended. Level of confidence : High Level of consensus: High * NOTE: If the NK1 receptor antagonist is not available for AC chemotherapy, palonosetron is the preferred 5-HT 3 receptor antagonist. ANTIEMETIC GUIDELINES: MASCC/ESMO COMMITTEE IV (1/3):

20. Guideline for the Prevention of Acute Nausea and Vomiting Following Chemotherapy of Moderate Emetic Risk: In patients who receive chemotherapy of moderate emetic risk, not including a combination of anthracycline plus cyclophosphamide, palonosetron plus dexamethasone is recommended for prophylaxis of acute nausea and vomiting. Level of confidence : Moderate Level of consensus: Moderate ANTIEMETIC GUIDELINES: MASCC/ESMO COMMITTEE IV (2/3):

21. Guideline for the Prevention of Acute Nausea and Vomiting Following Chemotherapy of Moderate Emetic Risk: The recommended dose of dexamethasone for prophylaxis of acute nausea and vomiting from chemotherapy of moderate emetic risk is 8 mg intravenously x 1. Level of confidence : Moderate Level of consensus: High ANTIEMETIC GUIDELINES: MASCC/ESMO COMMITTEE IV (3/3):

22. 5HT3DEXAPR 5HT3DEXAPR PALODEX + + ++ + AGENTROUTEANTIEMETICS Ondansetron IV8 mg or 0.15 mg/Kg Oral16 mg* Granisetron IV1 mg or 0.01 mg/Kg Oral2 mg (or 1 mg**) DolasetronOral100 mg*** Tropisetron IV5 mg Oral5 mg Palonosetron IV0.25 mg Oral0.5 mg Recommended Doses of Serotonin Receptor (5-HT 3 ) Antagonists for Acute Emesis * Randomized studies have tested the 8 mg twice daily schedule ** The 1 mg dose preferred by some panelists *** Oral dosing recommended rather than IV due to potential QT interval prolongation

23. Recommended Corticosteroid* (dexamethasone) Dosing DEXAMETHASONEDose and Schedule High Risk - Acute Emesis 20 mg once (12 mg when used with aprepitant or fosaprepitant)** - Delayed Emesis 8 mg bid for 3 - 4 days (8 mg once daily when used with aprepitant or fosaprepitant) Moderate Risk - Acute Emesis8 mg once - Delayed Emesis 8 mg daily for 2 - 3 days (many panelists give the dose as 4 mg bid) Low Risk - Acute Emesis4 - 8 mg once * While corticosteroids other than dexamethasone are effective antiemetics, the dose and schedule of dexamethasone coupled with its wide availability in various dose forms established it as the guideline agent of choice ** The 12 mg dose of dexamethasone is the only one tested with aprepitant in large randomized trials

24. Recommended NK 1 Receptor Antagonist Dosing* APREPITANT and FOSAPREPITANT** Dose and Schedule - Acute Emesis Aprepitant: 125 mg orally, once on the day of chemotherapy - or - Fosaprepitant: 150 mg IV, once on the day of chemotherapy - Delayed Emesis Aprepitant 80 mg orally, once daily for the 2 days after chemotherapy; or none if Fosaprepitant is used** * As of this update, Aprepitant and Fosaprepitant are the only approved antiemetic NK 1 antagonists. ** Fosaprepitant is an intravenously administered pro-drug of aprepitant. In the countries in which fosaprepitant is available, it is indicated to replace the three-day course of oral aprepitant (125 mg) only. It should be administered at a dose of 150mg IV on day 1 ONLY. If aprepitant is used on the day of chemotherapy, it should be followed on each of the next two days by oral aprepitant 80 mg daily. [Fosaprepitant was approved on its similar pharmacokinetic profile (Lasseter et al. J Clin Pharm. 47, 834 - 840; 2007) when tested against aprepitant, not by comparative antiemetic clinical trials].

25. Guideline for the Prevention of Delayed Nausea and Vomiting Following Chemotherapy of Moderate Emetic Risk: Patients who receive moderately emetic chemotherapy known to be associated with a significant incidence of delayed nausea and vomiting should receive antiemetic prophylaxis for delayed emesis. Level of confidence : High Level of consensus: High ANTIEMETIC GUIDELINES: MASCC/ESMO COMMITTEE V (1/3):

26. Guideline for the Prevention of Delayed Nausea and Vomiting Following Chemotherapy of Moderate Emetic Risk: In patients with breast cancer receiving a combination of anthracycline plus cyclophosphamide treated with a combination of aprepitant (or fosaprepitant), a 5-HT 3 receptor antagonist and dexamethasone to prevent acute nausea and vomiting, aprepitant* should be used to prevent delayed nausea and vomiting (*or none if fosaprepitant is used on day 1). MASCC Level of confidence : Moderate MASCC Level of consensus: Moderate ANTIEMETIC GUIDELINES: MASCC/ESMO COMMITTEE V (2/3):

27. Guideline for the Prevention of Delayed Nausea and Vomiting Following Chemotherapy of Moderate Emetic Risk: In patients receiving chemotherapy of moderate emetic risk (which does not include a combination of anthracycline plus cyclophosphamide) in which palonosetron is recommended, multiday oral dexamethasone treatment is the preferred treatment for the prevention of delayed nausea and vomiting. Level of confidence : Moderate Level of consensus: Moderate ANTIEMETIC GUIDELINES: MASCC/ESMO COMMITTEE V (3/3):

28. Guideline for prevention of acute nausea and vomiting in patients receiving low risk emetic agents: A single antiemetic agent such as dexamethasone, a 5-HT 3 receptor antagonist or a dopamine receptor antagonist, such as metoclopramide, is suggested for prophylaxis in patients receiving agents of low emetic risk. Level of confidence: No confidence possible Level of consensus: Moderate ANTIEMETIC GUIDELINES: MASCC/ESMO COMMITTEE VI (1/3):

29. 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. Level of confidence: No confidence possible Level of consensus: High ANTIEMETIC GUIDELINES: MASCC/ESMO COMMITTEE VI (2/3): *While unusual at this emetic level, if a patient experiences emesis it is advised that with subsequent chemotherapy treatments the regimen for the next higher emetic level should be given.

30. Guideline for prevention of delayed nausea and vomiting in patients receiving low or minimal risk antineoplastic agents*: No antiemetic should be administered for the prevention of delayed emesis induced by low or minimally emetic chemotherapy. Level of confidence: No confidence possible Level of consensus: High ANTIEMETIC GUIDELINES: MASCC/ESMO COMMITTEE VI (3/3): *While unusual at this emetic level, if a patient experiences emesis it is advised that with subsequent chemotherapy treatments the regimen for the next higher emetic level should be given.

31. Guideline for patients receiving multiple-day cisplatin: Patients receiving multiple-day cisplatin should receive a 5-HT 3 receptor antagonist plus dexamethasone for acute nausea and vomiting and dexamethasone for delayed nausea and vomiting. Level of confidence: High; Level of consensus: High For cisplatin given on days 1-5, the addition of an NK 1 receptor antagonist (aprepitant or fosaprepitant) could be considered starting no later that day 3. The optimal administration schedule for the NK 1 receptor antagonist is not yet defined. Level of confidence: Low; Level of consensus: Low ANTIEMETIC GUIDELINES: MASCC/ESMO COMMITTEE VII: No guideline was felt to be appropriate for rescue antiemesis or high-dose (i.e. transplant) chemotherapy. 5-HT 3 receptor antagonists should be dosed day 1-5, except for palonosetron that should be dosed on days 1, 3 and 5 only. NOTE:

32. Guidelines for prevention of anticipatory nausea and vomiting The best approach for anticipatory emesis is the best possible control of acute and delayed emesis. MASCC Level of confidence: High MASCC Level of consensus: High ANTIEMETIC GUIDELINES: MASCC/ESMO COMMITTEE VIII (1/2):

33. Guideline for the prevention of anticipatory nausea and vomiting Behavioral therapies, in particular progressive muscle relaxation training, systematic desensitization and hypnosis, can be used to treat anticipatory nausea and vomiting. Level of confidence: High Level of consensus: High Benzodiazepines are the only drugs that reduced the occurrence of anticipatory nausea and vomiting but their efficacy tended to decrease as chemotherapy treatments continue. Level of confidence: Moderate Level of consensus: Moderate ANTIEMETIC GUIDELINES: MASCC/ESMO COMMITTEE VIII (2/2):

34. Committee IXA (1/5): Levels of Emetic Risk with Radiation Therapy ANTIEMETIC GUIDELINES: MASCC/ESMO RISK LEVEL*AREA OF TREATMENT HIGHTBI, Total nodal irradiation MODERATEUpper abdomen, UBI, HBI LOW Cranium, craniospinal, H & N, lower thorax region, pelvis MINIMALExtremities, breast TBI: total body irradiation, HBI: half body irradiation, UBI: upper body irradiation * in concomitant radiochemotherapy the antiemetic prophylaxis is according to the chemotherapy-related antiemetic guidelines of the corresponding risk category, unless the risk of emesis is higher with radiotherapy than chemotherapy

35. Guideline for the prevention of nausea and vomiting in Patients receiving highly emetic radiation therapy: TBI, Total nodal irradiation Patients receiving highly emetic radiation therapy should receive a 5-HT 3 receptor antagonist plus dexamethasone. Level of confidence: High (Moderate with the addition of dexamethasone) Level of consensus: High ANTIEMETIC GUIDELINES: MASCC/ESMO COMMITTEE IXA (2/5):

36. Guideline for the prevention of nausea and vomiting in patients receiving moderately emetic radiation therapy: Upper abdomen, HBI, UBI Patients receiving moderately emetic radiation therapy should receive a 5-HT 3 receptor antagonist and optional short course dexamethasone. Level of confidence: High (Moderate with the addition of dexamethasone) Level of consensus: High ANTIEMETIC GUIDELINES: MASCC/ESMO COMMITTEE IXA (3/5):

37. Guideline for the prevention of nausea and vomiting in patients receiving radiation therapy of low emetic risk: Cranium, craniospinal, H & N, lower thorax region, pelvis Patients receiving radiation therapy of low emetic risk should receive prophylaxis or rescue with a 5-HT 3 receptor antagonist. Level of confidence: Moderate (Low for rescue) Level of consensus: High ANTIEMETIC GUIDELINES: MASCC/ESMO COMMITTEE IXA (4/5):

38. Guideline for the prevention of nausea and vomiting in patients receiving radiation therapy of minimal emetic risk: Extremities, breast Patients receiving radiation therapy of minimal emetic risk should receive rescue with a dopamine receptor-antagonist or a 5-HT 3 receptor antagonist. Level of confidence: Low Level of consensus: High ANTIEMETIC GUIDELINES: MASCC/ESMO COMMITTEE IXA (5/5):

39. Guideline for the prevention of nausea and vomiting following chemotherapy of high and moderate emetic risk in children: All pediatric patients should receive antiemetic prophylaxis with a combination of a 5-HT 3 receptor antagonist and dexamethasone. Level of confidence: Moderate Level of consensus: High ANTIEMETIC GUIDELINES: MASCC/ESMO COMMITTEE IXB (1/3): Antiemetics in Children

40. Guideline for the prevention of delayed nausea and vomiting following chemotherapy of high and moderate emetic risk in children: No appropriate studies are available for the prevention of delayed nausea and vomiting in children and therefore no formal recommendation is possible. Many panelists feel that in the absence of studies, children should be treated in a manner similar to that of adults receiving chemotherapy of this risk. Doses should be adjusted appropriately for children. ANTIEMETIC GUIDELINES: MASCC/ESMO COMMITTEE IXB (2/3): Antiemetics in Children

41. Guideline for the prevention of nausea and vomiting following chemotherapy of minimal and low emetic risk in children: No appropriate studies are available in this setting for children, and therefore no formal recommendation is possible. Many panelists feel that in the absence of studies, children should be treated in a manner similar to that of adults receiving chemotherapy of this risk. Doses should be adjusted appropriately for children. ANTIEMETIC GUIDELINES: MASCC/ESMO COMMITTEE IXB (3/3): Antiemetics in Children

42. MASCC/ESMO ANTIEMETIC GUIDELINE 2013 © 2013 Multinational Association of Supportive Care in Cancer TM All rights reserved worldwide.