EMETOGENICITY of CHEMOTHERAPY REGIMENS Version 2019

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A Pocket Guide To EMETOGENICITY OF CHEMOTHERAPY REGIMENS Version 2019

Overview Solid tumors Hematological malignancies Note to User

This pocket guide is designed as a practical tool for oncologists and aims to facilitate the decision-making process on antiemetic therapy for patients undergoing different chemotherapy (CT) regimens. Information is presented on the effect of different risk factors and CT regimens. However, this guide should not be considered as a tool for the choice of the CT regimen. Please consult guidelines and package inserts for exact dosages, notes and warnings on CT agents and combinations. This pocket guide includes information based on data from the latest ASCO, NCCN, and MASCC-ESMO guidelines; relevant evidences from the international scientific literature are also discussed. Abbreviations

5-HT3 5-hydroxytryptamine3 IV intravenous

AC anthracycline and cyclophosphamide LEC low emetogenic chemotherapy

ASCO American Society of Clinical Oncology Multinational Association for Supportive MASCC Care in Cancer CI continuous infusion MEC moderately emetogenic chemotherapy chemotherapy-induced nausea and CINV vomiting NCCN National Comprehensive Cancer Network

CT chemotherapy NCI National Cancer Institute

EC epirubicin and cyclophosphamide NK1 Neurokinin-1

ESMO European Society for Medical Oncology PO oral

HEC highly emetogenic chemotherapy RA receptor antagonist

Overview Solid tumors Hematological malignancies

OVERVIEW

• Introduction

• Emetogenicity of chemotherapy and classification

• Patient-related risk factors

• 5-HT3 receptor antagonists 5

• NK1 receptor antagonists

• NEPA 6

• CINV management

Solid tumors Hematological malignancies

• General

• High dose conditioning regimens for hematopoietic stem cell transplantation

References

Overview Solid tumors Hematological malignancies Overview

Introduction Despite advances in both cytotoxic therapy and supportive care, too many oncological patients undergoing chemotherapy (CT) still suffer from chemotherapy-induced nausea and vomiting (CINV), a condition associated with serious consequences to the patients’ health status and quality of life. It has been estimated that more than 50% of patients undergoing highly emetogenic chemotherapy (HEC) or moderately emetogenic chemotherapy (MEC) experience these side effects.1-2 For this reason, recent Guidelines issued by major oncological societies have stressed the importance of preventing CINV.3-5 The immediate impact of chemotherapy-induced nausea and vomiting (CINV) on Quality of Life (QoL) is clear. This has been highlighted by a study in which 70 ovarian cancer patients were asked to rank different effects of chemotherapy, from perfect health to death.6 Complete control of nausea and vomiting was ranked near perfect health, while severe delayed CINV was ranked close to death. However, healthcare providers often underestimate the incidence of CINV in cancer patients and the importance of effective management of this condition.2,7,8 Emetogenicity of chemotherapy and classification In addition, each CT agent has an intrinsic propensity to cause CINV, the intensity of which depends on the class and dose of drug administered. The intrinsic emetogenicity of a given anticancer agent should therefore serve as a major determinant in guiding decisions about antiemetic prophylaxis. Several international organizations have developed evidence-based antiemetic guidelines. MASCC/ESMO have included a rating system for anticancer agents based on intrinsic emetogenicity (risk of acute [within the first 24 hours after CT administration] emesis without concomitant antiemetic treatment) of the individual agents.9 Tables 1 and 2 summarize the emetogenic risks for the individual agents after oral or intravenous administration.

Patient-related risk factors Antiemetic guidelines recognize the importance of patient-related risk factors, including female gender, age under 50, anxiety, history of nausea and vomiting in prior chemotherapy treatments, history of hyperemesis gravidarum, motion sickness or morning sickness and no or minimal prior history of alcohol use. It has also been observed that patients who are not well controlled during the first cycle of CT are more likely to develop CINV in subsequent cycles. However, the data are not adequate to form the basis of a formal recommendation.3-5,10,11

Overview Solid tumors Hematological malignancies 5-HT3 receptor antagonists

5-HT3 receptor antagonists (RAs) are considered to be the cornerstone of antiemetic regimens. As far as is known, the older generation of 5-HT3 RAs (dolasetron, granisetron, ondansetron, tropisetron) exhibits essentially the same emesis control.3-5 Palonosetron is a new generation 5-HT3 RA, and comparative studies with or without concomitant dexamethasone have demonstrated that this provides more effective emesis control than the older generation 5-H3 RAs. Some CT regimens are administered on consecutive days. There has been limited progress in the prophylaxis of nausea and emesis in patients receiving multiple-day CT, such as cisplatin. Current MASCC/ESMO guidelines recommend that patients receiving multiple-day cisplatin should receive a 5-HT3 RA plus dexamethasone for acute nausea and vomiting and dexamethasone for delayed symptoms.3 The latest version of the NCCN guidelines also recommends palonosetron and granisetron extended-release injection formulation as the preferred 5-HT3 RA when used as part of an antiemetic regimen that does not contain an NK1 RA. Adult patients who are treated with 4- or 5-day cisplatin regimens should be offered a three-drug combination of an NK1 receptor antagonist, a 5-HT3 receptor antagonist, and dexamethasone.5 NK1 receptor antagonist

The introduction of the NK1 RA class has been the most significant recent advance in antiemetic prophylaxis. NK1 RAs are known to act in preventing emesis by displacing substance P from its receptor, and significantly reduce acute and delayed emesis in patients receiving highly or moderately emetic chemotherapy compared with those 12-15 receiving only a 5-HT3 RA plus dexamethasone.

NK1 RAs include aprepitant, fosaprepitant, rolapitant, netupitant, and fosnetupitant. It is important to note that netupitant (or fosnetupitant) is only available in combination with palonosetron (NEPA) and not as a single agent. An intravenous fixed combination of fosnetupitant/palonosetron is now also available.4 The NCCN Antiemetic Guidelines consider carboplatin to be a HEC if the threshold of exposure is AUC ≥4, requiring the triple antiemetic combination of a NK1 RA, 5HT3 RA and dex (while if <4 it is still considered as MEC).4 Furthermore, NCCN also recommends the addition of NK1 RA in MEC for selected patients with additional risk factors or previous treatment failure with a steroid plus 5-HT3 RA alone.

Overview Solid tumors Hematological malignancies 3-5 NK1 RAs recommendation for acute nausea and vomiting ASCO MASCC-ESMO NCCN Highly emetogenic chemotherapy (HEC) (including cisplatin) ✔ ✔ ✔ Anthracycline and cyclophosphamide based chemotherapya ✔ ✔ ✔ Carboplatin* ✔ ✔ ✔

Moderately emetogenic chemotherapy (MEC) ✔**

* Carboplatin is considered as “high-MEC” by ASCO (only when AUC ≥4) and MASCC-ESMO, and reclassified as HEC (when 3-5 AUC ≥4) by NCCN: an NK1 RA should be added in all cases.

** NCCN also recommends the use of NK1 RAs in MEC for selected patients with additional risk factors or previous therapy failure with 4 5-HT3 plus DEX alone. a HEC for all GLs with the only exception that MASCC/ESMO ones separate the recommendations in non-AC HEC and AC-HEC. NEPA NEPA is the first antiemetic combination agent developed, and comprises of the highly selective NK1 RA, netupitant, and the pharmacology clinically different 5-HT3 RA, palonosetron.16 A major advantage of this oral fixed combination is the convenience of administration, which may reduce potential dosing errors and increase treatment compliance by patients. Furthermore, the observed therapeutic effects in preventing CINV during the acute and delayed phases support the clinical use of the fixed combination NEPA for overall CINV control.17 If administered as a single oral dose prior to chemotherapy, in combination with oral dexamethasone, NEPA 300 mg showed superiority over oral palonosetron plus dexamethasone for all key efficacy endpoints during the delayed phase and throughout the 5 days following either cisplatin-based highly emetogenic chemotherapy or AC (cyclophosphamide, anthracycline) chemotherapy.16 The international guidelines endorse NEPA as a recommended option in the HEC 3-5 (and AC) setting. As a fixed NK1RA/5HT3RA combination in a single capsule given once/cycle, NEPA offers patients an effective convenient antiemetic prophylaxis that may offer an advantage over a standard 3-day APR/GRAN regimen (especially in prevention of nausea) in patients receiving high doses of cisplatin-based HEC.18

Overview Solid tumors Hematological malignancies As per GLs the triplet is recommended in all the high risk categories but NEPA is the only one who continue to protect against CINV (especially nausea) in high dose cisplatin HEC, which is more difficult to be controlled. NEPA is a recommended option in ASCO and MASCC/ESMO guidelines in the carboplatin-based regimen – which has re-classified as “high MEC” with specific 3,5 recommendations to treat with NK1 RA+5-HT3 RA+DEX – as well as in the HEC setting. Overview of NCCN / ASCO / MASCC-ESMO guidelines for acute nausea and vomiting3-5

Emetic risk groups Antiemetics

High (Non-AC) 5-HT3 RA + DEX + NK1 RA + OLA* High: anthracycline + 5-HT3 RA + DEX + NK1 RA + OLA* cyclophosphamide (AC)a

b d Carboplatin 5-HT3 RA + DEX + NK1 RA

c Moderate 5-HT3 RA + DEX + OLA*

e Low 5-HT3 RA or DEX or DRA

NK1 RA= DRA = 5-HT3 RA = DEX = neurokinin PALO = dopamine OLA = serotonin receptor dexamethasone 1 receptor palonosetron receptor Olanzapina antagonist antagonist antagonist

* The addition of OLA is recommended in HEC by ASCO, is one possible option in HEC and MEC by NCCN and only when nausea is an issue by MASCC/ESMO. a If an NK1 RA is not available for AC chemotherapy, palonosetron is the preferred 5-HT3 RA for MASCC/ESMO. b Carboplatin is considered as “high-MEC” by ASCO (here only AUC ≥4) and MASCC/ESMO, and reclassified as HEC by NCCN (when AUC ≥4): an NK1 RA should be added in all cases. c An NK1 RA is recommended as option in MEC for selected patients with additional risk factors or who have failed previous therapy with 5-HT3 antagonist plus steroid by NCCN. d Palonosetron and granisetron extended-release injection formulation are the preferred 5-HT3 RAs in MEC regimens without an NK1 RA by NCCN. e Not for ASCO.

Overview Solid tumors Hematological malignancies Overview of NCCN / ASCO / MASCC-ESMO guidelines for delayed nausea and vomiting3-5

Emetic risk groups Antiemetics

High (Non-AC) NK1 RAª + DEX + OLA* High: anthracycline + NK1 RAª ± DEX** + OLA* cyclophosphamide (AC)

b Carboplatin NK1 RAª + DEX + OLA* Moderatec DEX + OLA* Low -

* The addition of OLA is recommended in HEC by ASCO, is one possible option in HEC and MEC by NCCN and only when nausea is an issue by MASCC/ESMO. ** DEX is recommended in AC by NCCN and, if APR on Day 1, APR or DEX by MASCC/ESMO. a NK1 RA (aprepitant 80 mg) only if aprepitant 125 mg was used on Day 1. Other NK1 RAs, netupitant, rolapitant, aprepitant 165 mg or fosaprepitant 150 mg do not need repeat doses. b Carboplatin: DEX is recommended only by NCCN over AUC ≥4. c Only for regimens with known delayed CINV potential by MASCC/ESMO and ASCO.

CINV management Prophylactic control of CINV is a desirable goal in all patients at risk of developing CINV from the first cycle of CT. The decision about the optimal prophylaxis should be guided by two considerations: the emetic risk of the regimen and whether there is a substantial risk of delayed nausea and vomiting. This approach may make it possible to tailor the appropriate antiemetic regimen to individual patients who could benefit from extended or brief antiemetic coverage.

Solid tumors

CINV remains an important problem in the treatment of solid tumors, although single and combination treatments must be considered separately. Tables 1 and 2 give the emetic risk for single anticancer agents for adults after intravenous and oral administration, respectively. Table 3 gives the emetic risk for combination chemotherapy used in the treatment of solid tumors.

Overview Solid tumors Hematological malignancies In addition to the emetogenicity of each drug, other treatment-related factors should be taken into consideration. In particular, the dose and schedule used have major importance. For example, an agent with a low emetic risk when given alone may cause an increase in the potential to induce emesis when given at high doses or within combination regimens.3-5

The emetic risks of combination CT regimens commonly used in the treatment of non- hematologic malignancies are listed in Table 3. It is important to note that the tables do not intend to be an exhaustive compendium of CT regimens used in the treatment of cancer patients. Only regimens considered to induce a substantial (high to moderate) risk of emesis are listed. Please consult international treatment guidelines by tumor type for any unreported regimen, as well as the reference section for dosing schedules of the individual regimens listed in Table 3. It is important to remember that the present tool should only be used to guide decisions about antiemetic prophylaxis, and not as a decision tool for the selection of the anticancer therapy. Hematological malignancies

General Hematological malignancies are widespread cancers associated with high mortality rates, and require intensive treatment.19 Many patients undergoing treatment for hematological malignancies are at high risk of CINV. In addition, there are also clear treatment-related risk factors, such as the frequent use of highly emetogenic agents and the prescription of combination and/or multiple-day CT regimens. Adequate prevention of CINV is therefore of particular importance in the management of hematological malignancies. Table 4 summarizes the emetic risk of combination chemotherapy regimens used in the treatment of hematologic cancers.

High dose conditioning regimens for hematopoietic stem cell transplantation Autologous and allogeneic stem cell transplantation are increasingly being adopted in the management of several hematopoietic malignancies. Unfortunately, only a small

Overview Solid tumors Hematological malignancies minority of patients, about 20%, are completely protected from CINV associated with pre-transplant conditioning CT.20 There are many reasons for this, related to both the design of conditioning regimens and the unusual clinical profile of patients undergoing stem cell transplantation. Conditioning regimens typically consist of single, but more frequently, multiple agents given at very high doses over a multi-day schedule of 2 to 7 days. All drugs are highly emetogenic as single agents at the employed doses and their use in combination over several days multiplies the emetic risk of such regimens, particularly for delayed emesis.21 The disruption of the gastrointestinal mucosa, a late event associated with high dose conditioning, might further enhance substance P-related mechanisms of delayed nausea and vomiting. Patients undergoing conditioning have usually been treated with at least two previous lines of highly and/or moderately emetic CT, often in a multi-day schedule, and are concomitantly being given other emetogenic agents, including multiple intravenous antimicrobial therapy and opioids. Such patients also suffer from difficult psychological and environmental conditions (anxiety, depression, isolation, dietary restrictions, and sleep disturbances), which further promote and sustain severe emesis. Individual risk factors for CINV for hematologic patients undergoing stem cell transplantation are summarized below: Risk factors for CINV Comments Young age Eligibility for the procedure Previous exposure to multiple lines of highly emetogenetic or moderately emetogenetic multi-day chemotherapy (high risk or previous poorly Front line therapy, savage therapy (stem cell-mobilizing chemotherapy) controlled acute and delayed CINV) Combination of highly emetogenetic agents over a multi-day schedule of 2-7 Design of pre-transplant high-dose conditioning regimens days (acute and delayed CINV) Presence of Total Body Irradiation in conditioning regimens for allogeneic Total Body Irradiation is associated with a very high risk of acute and delayed stem cell transplantation emesis Exposure to dimethyl sulfoxide (DMSO) during stem cell reinfusion DMSO is an emetogenetic agent with a very disturbing smell Severe and prolonged damage to oral and gastrointestinal tract mucosae Promotion and maintenance of substance P-related mechanism of delayed (enteritis, mucositis) typically associated with high-dose conditioning CINV regimens (especially those including cytarabine) Concomitant and prolonged use of multiple intravenous antimicrobial Common to almost all patients from conditioning chemotherapy to prophylaxis/treatment (antibiotics, antifungals, antivirals) hematological recovery (engraftment) Use of analgesic opioids over a time-frame overlapping occurrence of Usually employed to control pain due to severe mucositis (i.e. high-dose delayed CINV melphalan conditioning) Isolation in air-filtered rooms (noise, smells, temperature, anxiety and During the period of post-conditioning bone marrow aplasia preceding other psycho-emotional issues) engraftment Dietary restrictions During post-conditioning neutropenia, mucositis, enteritis Use of steroids at variable doses and frequency as pre-medication for Confounding factor for estimating efficacy of antiemetic prophylaxis transfusion therapy

Table 5 summarizes the emetic risk of high dose chemotherapy programs most widely used as conditioning regimens for autologous cell transplantation. Given the unsatisfactory results of current antiemetic prophylaxis, prevention of nausea and vomiting in these patients is a typical unmet medical need. The MASCC/ESMO 3 committees have now issued formal recommendation to cover this setting.

Overview Solid tumors Hematological malignancies References

1. Cohen L, de Moor CA, Eisenberg P, Practice Guideline Update. J Clin Oncol vomiting (CINV): a comprehensive et al. Chemotherapy-induced nausea 2017; 35(28): 3240-61. review. Ann Oncol 2015; 26(6):1081- and vomiting: incidence and impact 6. Sun CC, Bodurka DC, Weaver CB, et al. 1090. on patient quality of life at community Rankings and symptom assessments 11. Molassiotis A, Lee PH, Burke TA, et al. oncology settings. Support Care Cancer of side effects from chemotherapy: Anticipatory Nausea, Risk Factors, and 2007; 15: 497-503. insights from experienced patients with Its Impact on Chemotherapy-Induced 2. Grunberg SM, Deuson RR, Mavros P, et ovarian cancer. Support Care Cancer Nausea and Vomiting: Results From the al. Incidence of chemotherapy-induced 2005; 13: 219-27. Pan European Emesis Registry Study. nausea and emesis after modern 7. Basch E. The missing voice of patients J Pain Symptom Manage 2016; 51(6): antiemetics. Cancer 2004; 100: 2261-8. in drug-safety reporting. NEJM 2010; 987-93. 3. Roila F, Molassiotis A, Herrstedt 362(10): 865-9. 12. AKYNZEO® SmPC 2015. J, et al. 2016 MASCC and ESMO 8. Di Maio M, Gallo C, Leighl NB, et al. 13. Hesketh PJ, Rossi G, Rizzi G, et guideline update for the prevention Symptomatic toxicities experienced al. Efficacy and safety of NEPA, of chemotherapy- and radiotherapy- during anticancer treatment: agreement an oral combination of netupitant induced nausea and vomiting and between patient and physician reporting and palonosetron, for prevention of of nausea and vomiting in advanced in three randomized trials. J Clin Oncol chemotherapy-induced nausea and cancer patients. Ann Oncol 2016; 2015; 33(8): 910-5. vomiting following highly emetogenic 27(suppl 5): v119-v133. Available at: 9. Grunberg SM, Warr D, Gralla RJ, et al. chemotherapy: a randomized dose- www.mascc.org/antiemetic-guidelines. Evaluation of new antiemetic agents ranging pivotal study Ann Oncol 2014; 4. NCCN clinical practice guidelines and definition of antineoplastic agent 25(7): 1340-6. in oncology, Antiemesis V3. 2018. emetogenicity – state of the art. Supp 14. Aapro M, Rugo H, Rossi G, et al. A Available at: www.nccn.org/ Care Cancer 2011; 19 (suppl 1): randomized phase III study evaluating professionals/physician_gls/pdf/ S43-S47. Available at: www.mascc.org. the efficacy and safety of NEPA, a antiemesis.pdf. 10. Jordan K, Jahn F, Aapro M. Recent fixed dose combination of netupitant 5. Hesketh PJ, et al. Antiemetics: American developments in the prevention of and palonosetron, for prevention Society of Clinical Oncology Clinical chemotherapy-induced nausea and of chemotherapy-induced nausea and vomiting following moderately 17. Gilmore J, Bernareggi A. 19. Schwartzberg LS, Jacobs P, Matsouka emetogenic chemotherapy. Ann Oncol Complementary pharmacokinetic P, et al. The role of second-generation 2014; 25(7): 1328-33. profiles of netupitant and palonosetron 5-HT3 receptor antagonists in managing 15. Gralla RJ, Bosnjak SM, Hontsa A, support the rationale for their oral chemotherapy-induced nausea and et al. A phase III study evaluating fixed combination for the prevention vomiting in hematological malignancies. the safety and efficacy of NEPA, a of chemotherapy-induced nausea and Crit Rev Oncol Hematol 2012; 83: 59-70. fixed-dose combination of netupitant vomiting. J Clin Pharmacol 2018 Nov 9. 20. Trigg ME, Inverso DM. Nausea and and palonosetron, for prevention of doi: 10.1002/jcph.1338. vomiting with high-dose chemotherapy chemotherapy-induced nausea and 18. Dechaphunkul A, Lu S, Olivari S, and stem cell rescue therapy: a review vomiting over repeated cycles of Zhang L. Efficacy of single dose NEPA, of antiemetic regimens. Bone Marrow chemotherapy. Ann Oncol 2014; 25(7): a fixed combination of netupitant and Transplant 2008; 42(8): 501-6. 1333-9. palonosetron, versus a 3-day regimen 21. Mirabile A, Celio L, Magni M, et al. 16. Jordan K, et al. Recent developments of aprepitant/granisetron (APR/GRAN) Evaluation of an every-other-day in the prevention of chemotherapy- for prevention of nausea in patients palonosetron schedule to control induced nausea and vomiting (CINV): A receiving high dose cisplatin. ESMO emesis in multiple-day high-dose comprehensive review. Ann Oncol 2015; Asia Congress, 23-25 November 2018. chemotherapy. Future Oncol 2014; 26(6): 1081-90. Poster No. 428P. 10(16): 2569-78.

Overview Solid tumors Hematological malignancies

Solid tumors

Overview Solid tumors Hematological malignancies Table 1 • Emetic risk of single intravenous anticancer agents

Emetic risk Antiemetic prophylaxis including Agent category NK1 RA recommendation by Anthracycline/cyclophosphamide combination* Carmustine HIGH Cisplatin Risk in nearly all Cyclophosphamide ≥1500 mg/m² ASCO MASCC/ESMO NCCN patients (>90%) Dacarbazine Mechlorethamine Streptozocin HIGH/HIGHLY § Carboplatin ASCO MASCC/ESMO NCCN MODERATE Carmustine** Azacitidine Bendamustine Clofarabine Cyclophosphamide <1500 mg/m² Cytarabine >1000 mg/m² Daunorubicin Doxorubicin MODERATE Epirubicin Risk in 30% to 90% NCCN# Idarubicin of patients Ifosfamide Irinotecan Oxaliplatin Romidepsin Temozolomide*** Thiotepa Trabectedin Aflibercept Belinostat Blinatumomab Bortezomib Brentuximab Cabazitaxel Carfilzomib Catumaxumab Cetuximab Cytarabine ≤1000 mg/m² Docetaxel Eribulin Etoposide LOW 5-Fluorouracil Gemcitabine Risk in 10% to Ipilimumab 30% of patients Ixabepilone Methotrexate Mitomycin Mitoxantrone Nab-paclitaxel Paclitaxel Panitumumab Pemetrexed Pegylated liposomal doxorubicin Pertuzumab Temsirolimus Topotecan Trastuzumab-emtansine Vinflunine

Overview Solid tumors Hematological malignancies Emetic risk Antiemetic prophylaxis including Agent category NK1 RA recommendation by Alemtuzumaba Bevacizumab Bleomycin Busulfan 2-Chlorodeoxyadenosine Cladribine Fludarabine MINIMAL Nivolumab Fewer than 10% Ofatumumab at risk Pembrolizumab Pixantrone Pralatrexate Rituximab Trastuzumab Vinblastine Vincristine Vinorelbine

* The combination of an anthracycline and cyclophosphamide in patients with breast cancer should be considered highly emetogenic. ** Carmustine >250 mg/m2 is considered as “high-MEC” and carmustine ≤250 mg/m2 is considered as MEC by NCCN. *** No direct evidence found for temozolomide IV. Classification is based on oral temozolomide, since all sources indicate a similar safety profile. # NK1 RA is a recommended option by NCCN in MEC for selected patients with additional risk factors or previous therapy failure with 5-HT3 plus DEX alone. NEPA is a recommended option in MEC without that limitation. § Carboplatin is considered as “high-MEC” by ASCO (only when AUC ≥4) and MASCC-ESMO, and reclassified as HEC (when AUC ≥4) by NCCN: an NK1 RA should be added in all cases. a Moderate for MASCC and ASCO.

Reference Roila F et al. Ann Oncol 2016;27(suppl 5):v119-v133. Available at: www.mascc.org/antiemetic-guidelines NCCN clinical practice guidelines in oncology, Antiemesis V3. 2018. Available at: www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf Hesketh PJ, et al. J Clin Oncol 2017; 35(28):3240-61 Table 2 • Emetic risk of single oral anticancer agents

Antiemetic prophylaxis including Emetic risk Agent category NK1 RA recommendation by

HIGH Hexamethylmelamine ASCO MASCC/ESMO NCCN Risk in nearly all Procarbazine patients (>90%) Bosutinib Ceritinib MODERATE Crizotinib Risk in 30% to Cyclophosphamide NCCN# 90% of patients Imatinib Temozolomide Vinorelbine Afatinib Lenalidomide Axatinib Olaparib Capecitabine Nilotinib Dabrafenib Pazopanib LOW Dasatinib Ponatinib Risk in 10% to Everolimus Regorafenib 30% of patients Etoposide Sunitinib Fludarabine Tegafur Uracil Ibrutinib Thalidomide Idelalisib Vandetanib Lapatinib Vorinostat

Overview Solid tumors Hematological malignancies Antiemetic prophylaxis including Emetic risk Agent category NK1 RA recommendation by Chlorambucil Erlotinib Gefitinib Hydroxyurea Melphalan MINIMAL Methotrexate Fewer than 10% L-Phenylalanine mustard at risk Pomalidomide Ruxolitinib Sorafenib 6-Thioguanine Vemurafenib Vismodegib

# NK1 RA is a recommended option by in MEC for selected patients with additional risk factors or previous therapy failure with 5-HT3 plus DEX alone. NEPA is a recommended option in MEC without that limitation.

Days of Antiemetic prophylaxis 2 Most emetogenic Emetic risk Ref. N. Regimen Agent/dose (mg/m )/route administration including NK1 RA agent of the regimen* in a single cycle recommendation by Doxorubicin/75/IV 1 Moderate for A A followed by Cyclophosphamide/600/IV 1 Doxorubicin 1 Moderate for NCCN# CMF Methotrexate/40/IV 1 Cyclophosphamide CMF Fluorouracil/600/IV 1 Doxorubicin/60/IV 1 Doxorubicin ASCO MASCC/ESMO 2 AC High Cyclophosphamide/600/IV 1 Cyclophosphamide NCCN Doxorubicin/60/IV 1 Doxorubicin High for AC ASCO MASCC/ESMO 3 AC followed by D Cyclophosphamide/600/IV 1 Cyclophosphamide Low for D NCCN Docetaxel/100/IV 1 Doxorubicin/60/IV 1 Doxorubicin High for AC ASCO MASCC/ESMO 3 AC followed by T Cyclophosphamide/600/IV 1 Cyclophosphamide Low for T NCCN Paclitaxel/80/IV (weekly for 12 wks) Doxorubicin/60/IV 1 Dose-dense AC Doxorubicin High for AC ASCO MASCC/ESMO 4 Cyclophosphamide/600/IV 1 followed by T Cyclophosphamide Low for T NCCN Paclitaxel/175/IV 1 Doxorubicin/50/IV 1 5 AD Doxorubicin Moderate NCCN# Docetaxel/75/IV 1 Doxorubicin/50/IV 1 6 AT Doxorubicin Moderate NCCN# Paclitaxel/125-220/IV 1 Bleomycin/30 Units/IV 3 (days 1,8,15) ASCO MASCC/ESMO 7 BEP Etoposide/100 day/IV 5 (days 1-5) Cisplatin High NCCN Cisplatin/20 day/IV 5 (days 1-5) Cyclophosphamide/100 day/PO 14 (days 1-14) Cyclophosphamide ASCO MASCC/ESMO 8 CAF Doxorubicin/30/IV 2 (days 1,8) High Doxorubicin NCCN Fluorouracil/500/IV 2 (days 1,8) CapOx Capecitabine/2000 day/PO 14 (days 1-14) 9 Oxaliplatin Moderate NCCN# ±Bevacizumab Oxaliplatin/130/IV 1 Cyclophosphamide/1000/IV 1 Cyclophosphamide 10 CAV Doxorubicin/45/IV 1 Moderate*** NCCN# Doxorubicin Vincristine/1.4/IV 1

Overview Solid tumors Hematological malignancies Days of Antiemetic prophylaxis 2 Most emetogenic Emetic risk Ref. N. Regimen Agent/dose (mg/m )/route administration including NK1 RA agent of the regimen* in a single cycle recommendation by Carboplatin/AUC5-6/IV 1 11 Carbo+Docetaxel Carboplatin High/Moderate** ASCO MASCC/ESMO NCCN Docetaxel/60-75/IV 1 Carboplatin/AUC5-6/IV 1 12 Carbo+Etoposide Carboplatin High/Moderate** ASCO MASCC/ESMO NCCN Etoposide/100-120 day/IV 3 (days 1-3) Carbo+Gemcitabine Carboplatin/AUC5/IV 1 13 Carboplatin High/Moderate** ASCO MASCC/ESMO NCCN ±Bevacizumab Gemcitabine/1000 day/IV 2 (days 1,8) Carboplatin/AUC5/IV 1 Carboplatin 14 Carbo+Irinotecan High/Moderate** ASCO MASCC/ESMO NCCN Irinotecan/50/IV 3 (days 1,8,15) Irinotecan Carbo+Paclitaxel Paclitaxel/175-200/IV 1 15 Carboplatin High/Moderate** ASCO MASCC/ESMO NCCN ±Bevacizumab Carboplatin/AUC6/IV 1 Carbo+Paclitaxel Paclitaxel/175/IV 1 16 Carboplatin High/Moderate** ASCO MASCC/ESMO NCCN +Trastuzumab Carboplatin/AUC6/IV 1 Carbo+ Carboplatin/AUC5/IV 1 13 Carboplatin High/Moderate** ASCO MASCC/ESMO NCCN Pemetrexed Pemetrexed/500/IV 1 Carbo+ Carboplatin/AUC6/IV 1 17 Carboplatin High/Moderate** ASCO MASCC/ESMO NCCN Vinorelbine Vinorelbine/25 day/IV 3 (days 1,8,15) Cyclophosphamide/75 day/PO 14 (days 1-14) Cyclophosphamide 18 CEF Epirubicin/60/IV 2 (days 1,8) High ASCO MASCC/ESMO NCCN Epirubicin Fluorouracil/500/IV 2 (days 1,8) Cisplatin/80/IV 1 19 Cis+Capecitabine Cisplatin High ASCO MASCC/ESMO NCCN Capecitabine/2000 day/PO 14 (days 1-14) 20 Cis+Cetuximab Cisplatin/100/IV 1 Cisplatin High ASCO MASCC/ESMO NCCN Cisplatin/75/IV 1 21 Cis+Docetaxel Cisplatin High ASCO MASCC/ESMO NCCN Docetaxel/75/IV 1 Cisplatin/50/IV 1 22 Cis+Doxorubicin Cisplatin High ASCO MASCC/ESMO NCCN Doxorubicin/60/IV 1 Cisplatin/80/IV 1 23 Cis+Etoposide Cisplatin High ASCO MASCC/ESMO NCCN Etoposide/100 day/IV 3 (days 1-3) Cisplatin/25 day/IV 3 (days 1-3) 24 Cis+Etoposide Cisplatin High ASCO MASCC/ESMO NCCN Etoposide/100 day/IV 3 (days 1-3) Cisplatin/100/IV 1 25 Cis+Fluorouracil Cisplatin High ASCO MASCC/ESMO NCCN Fluorouracil/1000 day/CI 5 (days 1-5) Cisplatin/75/IV 1 26 Cis+Gemcitabine Cisplatin High ASCO MASCC/ESMO NCCN Gemcitabine/1000-1250/IV 2 (days 1,8) Cisplatin/25/IV 1 27 Cis+Gemcitabine Cisplatin High ASCO MASCC/ESMO NCCN Gemcitabine/1000/IV 2 (days 1,8) Cisplatin/60/IV 1 28 Cis+Irinotecan Cisplatin High ASCO MASCC/ESMO NCCN Irinotecan/60/IV 3 (days 1,8,15) Cisplatin/75/IV 1 29 Cis+Paclitaxel Cisplatin High ASCO MASCC/ESMO NCCN Paclitaxel/175/IV 1 Cisplatin/75/IV 1 26 Cis+Pemetrexed Cisplatin High ASCO MASCC/ESMO NCCN Pemetrexed/500/IV 1 Cisplatin/80/IV 1 30 Cis+Vinorelbine Cisplatin High ASCO MASCC/ESMO NCCN Vinorelbine/25/IV 2 (days 1,8) Cisplatin/20 day/IV 4 (days 1-4) Cisplatin 31 CIM Ifosfamide/1500 day/IV 4 (days 1-4) High ASCO MASCC/ESMO NCCN Ifosfamide (Mesna/IV) Cyclophosphamide/100 day/PO 14 (days 1-14) 32 CMF Methotrexate/40/IV 2 (days 1,8) Cyclophosphamide Moderate NCCN# Fluorouracil/600/IV 2 (days 1,8) Docetaxel/75/IV 1 33 DC Cyclophosphamide Moderate NCCN# Cyclophosphamide/600/IV 1 Docetaxel/75/IV 1 34 DC+Trastuzumab Carboplatin High/Moderate** ASCO MASCC/ESMO NCCN Carboplatin/AUC6/IV 1 Docetaxel/75/IV 1 25 DCF Cisplatin/75/IV 1 Cisplatin High ASCO MASCC/ESMO NCCN Fluorouracil/750 day/CI 5 (days 1-5) Epirubicin/75/IV 1 Epirubicin 35 EC High ASCO MASCC/ESMO NCCN Cyclophosphamide/600/IV 1 Cyclophosphamide

Overview Solid tumors Hematological malignancies Days of Antiemetic prophylaxis 2 Most emetogenic Emetic risk Ref. N. Regimen Agent/dose (mg/m )/route administration including NK1 RA agent of the regimen* in a single cycle recommendation by Epirubicin/50/IV 1 36 ECF Cisplatin/60/IV 1 Cisplatin High ASCO MASCC/ESMO NCCN Fluorouracil/200 day/CI 21 (days 1-21) Epirubicin/50/IV 1 36 ECX Cisplatin/60/IV 1 Cisplatin High ASCO MASCC/ESMO NCCN Capecitabine/1250 day/PO 21 (days 1-21) Epirubicin/50/IV 1 Epirubicin 36 EOX Oxaliplatin/130/IV 1 Moderate*** NCCN# Oxaliplatin Capecitabine/1250 day/PO 21 (days 1-21) Epirubicin/75/IV 1 35 ET Epirubicin Moderate NCCN# Paclitaxel/200/IV 1 Fluorouracil/500/IV 2 (days 1,8) Doxorubicin 37 FAC Doxorubicin/50/IV 1 High ASCO MASCC/ESMO NCCN Cyclophosphamide Cyclophosphamide/500/IV 1 Fluorouracil/500/IV 1 Epirubicin 38 FEC Epirubicin/100/IV 1 High ASCO MASCC/ESMO NCCN Cyclophosphamide Cyclophosphamide 500/IV 1 Fluorouracil/500/IV 1 FEC followed Epirubicin/100/IV 1 Epirubicin High for FEC 38 ASCO MASCC/ESMO NCCN by D Cyclophosphamide/500/IV 1 Cyclophosphamide Low for D Docetaxel/100/IV 1 Fluorouracil/400/IV 1 FOLFIRI± Leucovorin/400/IV 1 39 a) Bevacizumab Irinotecan Moderate NCCN# Fluorouracil/1200 day/CI 2 (days 1,2) b) Cetuximab Irinotecan/180/IV 1 Fluorouracil/400 day/IV 2 (days 1,2) FOLFOX-4± Leucovorin/200 day/IV 2 (days 1,2) 40 a) Bevacizumab Oxaliplatin Moderate NCCN# Fluorouracil/600 day/CI 2 (days 1,2) b) Cetuximab Oxaliplatin/85/IV 1 Irinotecan/165/IV 1 Oxaliplatin/85/IV 1 Irinotecan 41 FOLFOXIRI Fluorouracil/400 day/IV 1 Moderate** NCCN# Oxaliplatin Leucovorin/200/IV 1 Fluorouracil/1600 day/CI 2 (days 1,2) Oxaliplatin/85/IV 1 Leucovorin/400/IV 1 Oxaliplatin 42 FOLFIRINOX Irinotecan/180/IV 1 Moderate** NCCN# Irinotecan Fluorouracil/400 day/IV 1 Fluorouracil/1200 day/CI 2 (days 1,2) GEMOX Gemcitabine/1000/IV 2 (days 1,8) 43 (refractory Oxaliplatin/130/IV 1 Oxaliplatin Moderate NCCN# testicular cancer) Ifosfamide/1600 day/IV 3 (days 1-3) Ifosfamide+ 44 Paclitaxel/135/IV 1 Ifosfamide Moderate # Paclitaxel NCCN (Mesna/IV) Irinotecan Irinotecan/250/IV (Cycle1) 1 45 Irinotecan Moderate # +Cetuximab Irinotecan/350/IV (Cycle 2) 1 NCCN Fluorouracil/400/IV 1 Leucovorin/400/IV 1 46 mFOLFOX-6 Oxaliplatin Moderate # Fluorouracil/1200 day/CI 2 (days 1,2) NCCN Oxaliplatin/85/IV 1 Docetaxel/75/IV 1 Doxorubicin 47 TAC Doxorubicin/50/IV 1 High ASCO MASCC/ESMO NCCN Cyclophosphamide Cyclophosphamide/500/IV 1 Paclitaxel/160/IV 1 22 TAP Doxorubicin/45/IV 1 Cisplatin High ASCO MASCC/ESMO NCCN Cisplatin/50/IV 1 Paclitaxel/250/IV 1 (Mesna/IV) Cisplatin 48 TIP (mod. NCCN) High ASCO MASCC/ESMO NCCN Ifosfamide/1500 day/IV 4 (days 2-5) Ifosfamide Cisplatin/25 day/IV 4 (days 2-5)

Overview Solid tumors Hematological malignancies Days of Antiemetic prophylaxis 2 Most emetogenic Emetic risk Ref. N. Regimen Agent/dose (mg/m )/route administration including NK1 RA agent of the regimen* in a single cycle recommendation by Trabectedin+ Trabectedin/1.1/IV/CI 1 Pegylated PLD/30/IV 1 49 Trabectedin Moderate # liposomal NCCN doxorubicin (PLD) Vinblastine/0.11mg/kg day/IV 2 (days 1,2) (Mesna/IV) Cisplatin 50 VeIP High ASCO MASCC/ESMO NCCN Ifosfamide/1200 day/IV 5 (days 1-5) Ifosfamide Cisplatin/20 day/IV 5 (days 1-5) Etoposide/75-100 day/IV 5 (days 1-5) (Mesna/IV) Cisplatin 51 VIP High ASCO MASCC/ESMO NCCN Ifosfamide/1200 day/IV 5 (days 1-5) Ifosfamide Cisplatin/20 day/IV 5 (days 1-5)

* Patients receiving multi-day chemotherapy are at risk for both acute and delayed nausea and emesis based upon the emetogenic potential of the individual agents and their sequence. IV, intravenous; CI, continuous infusion; PO, oral. References for combination chemotherapy regimens. ** Carboplatin is considered as “high-MEC” by ASCO (only when AUC ≥4) and MASCC-ESMO, and reclassified as HEC (when AUC ≥4) by NCCN: an NK1 RA should be added in all cases. *** Clinician should consider that a combination of two moderately emetogenic agents can result in an increased emetic risk of chemotherapy regimen. # NK1 RA is a recommended option by NCCN in MEC for selected patients with additional risk factors or previous therapy failure with 5-HT3 plus DEX alone. NEPA is a recommended option in MEC without that limitation. Hematological malignancies

Overview Solid tumors Table 4 • Emetic risk of combination chemotherapy regimens used in the treatment of hematologic cancers in adults (regimens listed in alphabetical order)

Days of Antiemetic prophylaxis 2 Most emetogenic Emetic risk Ref. N. Regimen Agent/dose (mg/m )/route administration including NK1 RA agent of the regimen* in a single cycle recommendation by 52, 53, 54 Azacitidine 5-Azacitidine/75/SC 7 (days 1-7) 5-Azacitidine Moderate NCCN# Doxorubicin/25/IV 2 (days 1,15) Bleomycin/10 Units/IV 2 (days 1,15) 55 ABVD Dacarbazine High ASCO MASCC/ESMO NCCN Vinblastine/6/IV 2 (days 1,15) Dacarbazine/375/IV 2 (days 1,15) Bleomycin/10 Units/IV 1 Etoposide/100 day/IV 3 (days 1-3) Doxorubicin/25/IV 1 BEACOPP 56 Cyclophosphamide/650/IV 1 Procarbazine High ASCO MASCC/ESMO NCCN Basis Vincristine/1.4/IV 1 Procarbazine/100 day/PO 7 (days 1-7) Prednisone/40/IV 14 (days 1-14) Bleomycin/10 Units/IV 1 Etoposide/200 day/IV 3 (days 1-3) Doxorubicin/35/IV 1 BEACOPP 56 Cyclophosphamide/1250/IV 1 Procarbazine High ASCO MASCC/ESMO NCCN (escalated-dose) Vincristine/1.4/IV 1 Procarbazine/100 day/PO 7 (days 1-7) Prednisone/40/IV 14 (days 1-14) 57, 58, Bendamustine Bendamustine alone/100/IV 2 (days 1-2) Bendamustine Moderate NCCN# 59, 60 ±Rituximab Bendamustine(+Rituximab)/90/IV 2 (days 2-3) Cyclophosphamide/750/IV 1 Liposomal doxorubicin/30/IV 1 61 CDOP+Rituximab Cyclophosphamide Moderate NCCN# Vincristine/1.4/IV 1 Prednisone/40 day/PO 5 (days 1-5) Cyclophosphamide/750/IV 1 Epirubicin/70/IV 1 62 CEOP Cyclophosphamide Moderate NCCN# Vincristine/1.4/IV 1 Prednisone/100/PO 5 (days 1-5) Cyclophosphamide/600 day/IV 2 (days 1,8) CEPP Etoposide/70 day/IV 3 (days 1-3) 63 Procarbazine High ASCO MASCC/ESMO NCCN ±Rituximab Procarbazine/60 day/PO 10 (days 1-10) Prednisone/60 day/PO 10 (days 1-10) Cyclophosphamide/750/IV 1 Doxorubicin/50/IV 1 CHOP Cyclophosphamide 64 Vincristine/1.4/IV 1 Moderate NCCN# ±Rituximab Doxorubicin Prednisone/100 mg absolute day/ 5 (days 1-5) PO Cyclophosphamide/750/IV 1 Doxorubicin/50/IV 1 CHOEP Vincristine/1.4/IV 1 Cyclophosphamide 65 Moderate NCCN# ±Rituximab Etoposide/100/IV 3 Doxorubicin Prednisone/100 mg absolute day/ 5 PO Cyclophosphamide/600/IV 1 Mitoxantrone/10/IV 1 66 CNOP Cyclophosphamide Moderate NCCN# Vincristine/1/IV 1 Prednisolone/40 mg day/PO 5 (days 1-5) Cyclophosphamide/800/IV 1 (day 1) Vincristine/1.5/IV 2 (days 1,8) Doxorubicin/40/IV 1 (day 1) Cytarabine/70mg/IT 2 (days 1,3) Cyclophosphamide/200 day/IV 4 (days 2-5) Cyclophosphamide CODOX-M 67 Methotrexate/100-300/IV 1 (day 10) Doxorubicin High ASCO MASCC/ESMO NCCN (dose-modified) Methotrexate/900-2700/IV 1 (day 10) Methotrexate Leucovorin/15/IV (see reference) Methotrexate/12mg/IT 1 (day 15) Leucovorin/15mg/PO 1 (day 16) (alternating with IVAC, see below)

Cyclophosphamide/750/IV 1 Cyclophosphamide COMP Liposomal doxorubicin/50/IV 1 68, 69 Liposomal Moderate NCCN# +Rituximab Vincristine/1.4/IV 1 doxorubicin Prednisone/40 day/PO 5 (days 1-5) Cyclophosphamide/750 day/IV 1 CVP Vincristine/1.4/IV 1 70 Cyclophosphamide Moderate NCCN# ±Rituximab Prednisone/100 mg absolute 5 (days 1-5) day/PO Etoposide/65 day/CI 3 (days 2-4) Prednisone/60 day/PO 14 (days 1-14) DA-EPOCH Cyclophosphamide 71 Vincristine/0.5 day/CI 3 (days 2-4) Moderate NCCN# ±Rituximab Doxorubicin Cyclophosphamide/750/IV 1 Doxorubicin/15 day/CI 3 (days 2-4) Dexamethasone/40mg day/IV 4 (days 1-4) Cyclophosphamide/400 day/CI 4 (days 1-4) Cisplatin 72 DCEP High ASCO MASCC/ESMO NCCN Etoposide/40 day/CI 4 (days 1-4) Cyclophosphamide Cisplatin/10 day/CI 4 (days 1-4) 73, 74, Decitabine/20/IV 5 (days 1-5) Decitabine Decitabine Moderate NCCN# 75 Decitabine/15 thrice daily/IV 3 (days 1-3) Dexamethasone/40mg absolute DHAP day/PO or IV 4 (days 3-6) 76 Cisplatin High ASCO MASCC/ESMO NCCN ±Rituximab Cisplatin/100/CI 1 Cytarabine/2000 bid/IV 1 Dexamethasone/40mg day/PO 4 (days 1-4) Thalidomide/400mg day/PO (daily) Cisplatin Cisplatin/10 day/CI 4 (days 1-4) 77 DT-PACE Cyclophosphamide High ASCO MASCC/ESMO NCCN Doxorubicin/10 day/CI 4 (days 1-4) Doxorubicin Cyclophosphamide/400 day/CI 4 (days 1-4) Etoposide/40 day/CI 4 (days 1-4) Etoposide/60 day/IV 4 (days 1-4) ESHAP Prednisolone/250-500mg day/IV 4 (days 1-4) Cisplatin 78 High ASCO MASCC/ESMO NCCN ±Rituximab Cytarabine/2000/IV 1 Cytarabine Cisplatin/25 day/CI 4 (days 1-4) FC Fludarabine/25 day/IV 3 (days 1-3) 79 Cyclophosphamide Moderate NCCN# +Rituximab Cyclophosphamide/250 day/IV 3 (days 1-3) Fludarabine/25 day/IV 3 (days 1-3) FCM 80 Cyclophosphamide/200 day/IV 3 (days 1-3) Cyclophosphamide Moderate NCCN# +Rituximab Mitoxantrone/6/IV 1 81 Fotemustine Fotemustine/120/IV 1 Fotemustine Moderate NCCN# GEMOX Gemcitabine/1000/IV 1 82 Oxaliplatin Moderate NCCN# +Rituximab Oxaliplatin/100/IV 1 GEMOX Gemcitabine/1200/IV 2 (days 1,8) 83 Oxaliplatin Moderate NCCN# +Rituximab Oxaliplatin/120/IV 1 (day 2) Gemcitabine/100/IV 1 (day 2) GIFOX Ifosfamide 84 Ifosfamide/5000/CI 1 (day 3) Moderate NCCN# +Rituximab Oxaliplatin Oxaliplatin/130/IV 1 (day 3) Gemcitabine/1000/IV 2 (days 1,8) GDP 85 Dexamethasone/40mg day/PO 4 (days 1-4) Cisplatin High ASCO MASCC/ESMO NCCN ±Rituximab Cisplatin/75/IV 1

Cycles 1, 3, 5, and 7: Cyclophosphamide/300 bid/IV 3 (days 1-3) (Mesna/IV) Vincristine/2mg/IV 2 (days 4,11) HyperCVAD Cyclophosphamide 86 Doxorubicin/50/CI 1 Moderate NCCN# ±Rituximab Doxorubicin Dexamethasone/40mg day/PO 8 (days 1-4, and or IV 11-14) (alternating with high-dose methotrexate and cytarabine) Ifosfamide/5000/IV 1 ICE (Mesna/IV) 1 Carboplatin High/ 87 ASCO MASCC/ESMO NCCN ±Rituximab Carboplatin/AUC5/IV 1 Ifosfamide Moderate** Etoposide/100 day/IV 3 (days 3-5)

Ifosfamide/2500 day/IV 3 (days 1-3) IEV Ifosfamide 88 Epirubicin/100/IV 1 Moderate NCCN# <60 years Epirubicin Etoposide/150/IV 3 (days 1-3) Ifosfamide/2000 day/IV 4 (days 1-4) Gemcitabine/800 day/IV 2 (days 1,4) 89 IGEV Ifosfamide Moderate NCCN# Vinorelbine/20/IV 1 Prednisolone/100mg day/PO or IV 4 (days 1-4) Ifosfamide/1500 day/IV 3 (days 1-3) Methotrexate/30/IV 2 (days 3,10) 90 IMEP Ifosfamide Moderate NCCN# Etoposide/100 day/IV 3 (days 1-3) Prednisolone/120mg day/PO 5 (days 1-5) Etoposide/60 day/IV 5 (days 1-5) Ifosfamide/1000-1500 day/IV 5 (days 1-5) (Mesna/IV) Cytarabine/1000-2000 day/IV 2 (days 1-2) Cytarabine 67 IVAC Moderate NCCN# Methotrexate/12mg/IT 1 (day 5) Ifosfamide Leucovorin/15mg/PO 1 (day 6) (alternating with CODOX-M, see above) Ifosfamide/3000 day/CIV 24 hrs 3 (days 1-3) Ifosfamide 91 IVE Epirubicin/50/IV 1 Moderate NCCN# Epirubicin Etoposide/200/IV 3 (days 1-3) (Mesna/IV) MINE Ifosfamide/1330 day/IV 3 (days 1-3) 92 Ifosfamide Moderate NCCN# ±Rituximab Mitoxantrone/8/IV 1 Etoposide/65 day/IV 3 (days 1-3) Carmustine/60/IV 1 Cytarabine/100 bid/IV 4 (days 2-5) Carmustine 93 Mini-BEAM High ASCO MASCC/ESMO NCCN Etoposide/75 day/IV 4 (days 2-5) Melphalan Melphalan/30/IV 1

PC Pentostatin/4/IV 1 94 Cyclophosphamide Moderate NCCN# +Rituximab Cyclophosphamide/600/IV 1

Chemo given weekly for 12 wks: Vinblastine/6/IV 1 (on wks 1,3,5,7,9,11) Doxorubicin/25/IV 1 (on wks 1,3,5,7,9,11) Vincristine/1.4/IV 1 (on wks 2,4,6,8,10,12) 95 Stanford V Mechloretamine High ASCO MASCC/ESMO NCCN Bleomycin/5 Units/IV 1 (on wks 2,4,6,8,10,12) Mechloretamine/6/IV 1 (on wks 1,5,9) Etoposide/60 bid/IV 1 (on wks 3,7,11) Prednisone/40/PO (see reference)

Bortezomib/1.6/IV 1, 8, 15, 22 VB 96 Bendamustine/90/IV 1,2 Bendamustine Moderate NCCN# +Rituximab (see reference)

Daunorubicin+ Daunorubicin/45 to 90/IV 3 (days 1-3) Daunorubicin 97 Moderate NCCN# Cytarabine Cytarabine /100 or 200 day/CI 7 (days 1-7) Cytarabine (200)

Idarubicin+ Idarubicin/12/IV 3 (days 1-3) 97 Idarubicin Moderate NCCN# Cytarabine Cytarabine /100 day/CI 7 (days 1-7)

High dose Cytarabine/1000-3000/ IV/q 3 to 6 (days 1-3 97, 98 Cytarabine Moderate NCCN# Cytarabine 12 hours or 1-6)

Fludarabine/30/IV 5 (days 1-5) 99 FLAG Cytarabine/2000/4-hour IV 5 (days 1-5) Cytarabine Moderate NCCN# G-CSF 5 μg/kg body weight SC 6 (-1-5)

100 Clofarabine Clofarabine/40 or 30/IV 5 (days 1-5) Clofarabine Moderate NCCN#

Clofarabine+ Clofarabine/40/IV 5 (days 2-6) Clofarabine 101 Moderate NCCN# Cytarabine Cytarabine/1000/2-hour IV 5 (days 1-5) Cytarabine

Cladribine Cladribrine/5.6/2-hour IV 5 102 Cladribine Minimal ±Rituximab

* Patients receiving multi-day chemotherapy are at risk for both acute and delayed nausea and emesis based upon the emetogenic potential of the individual agents and their sequence. ** Carboplatin is considered as “high-MEC” by ASCO (only when AUC ≥4) and MASCC-ESMO, and reclassified as HEC (when AUC ≥4) by NCCN: an NK1 RA should be added in all cases. # NK1 RA is a recommended option by NCCN in MEC for selected patients with additional risk factors or previous therapy failure with 5-HT3 plus DEX alone. NEPA is a recommended option in MEC without that limitation. Table 5 • Emetic risk of high-dose chemotherapy programs most widely used as conditioning regimens for autologous stem cell transplantation in adults (regimens listed in alphabetical order)

Days of Emetogenic Antiemetic prophylaxis Regimen 2 administration potential of single Emetic risk Ref. N. Agent/dose (mg/m )/route including NK1 RA (reference) (day 0: stem cells agents of the regimen§ recommendation by infusion) (descending order) Carmustine/300/IV -7 Carmustine* 103, Etoposide/800/IV -6 to -3 Cyclophosphamide* BEAC High ASCO MASCC/ESMO NCCN 104 Cytarabine/800/IV -6 to -3 Cytarabine** Cyclophosphamide/(35 mg/kg)/IV -6 to -3 Etoposide**

Carmustine/150/IV -7 and -6 or Carmustine* 103, Carmustine/300/IV -6 Melphalan** 104, BEAM High ASCO MASCC/ESMO NCCN Etoposide/200/IV -5 to -2 Cytarabine** 105 Cytarabine/400/IV -5 to -2 Etoposide** Melphalan/140/IV -1

Bendamustine/200/IV -7 and -6 Bendamustine* Etoposide/200/IV -5 to -2 Etoposide** 106 BeEAM High ASCO MASCC/ESMO NCCN Cytarabine/400/IV -5 to -2 Cytarabine** Melphalan/140/IV -1 Melphalan**

107, Busulphan/(4 mg/kg)/PO -6 to -4 Busulphan* 108, BuCy Cyclophosphamide/(60 mg/kg)/IV -2 to -1 High ASCO MASCC/ESMO NCCN Cyclophosphamide* 109

Busulphan/(3.2 mg/kg; q 6 hrs)/IV -7 to -4 Busulphan* 110 BuCy High ASCO MASCC/ESMO NCCN Cyclophosphamide/(120 mg/kg)/IV -3 and -2 Cyclophosphamide*

Busulphan/(0.8 mg/kg; q 6 hrs)/IV -7 to -5 Busulphan* 111 BuCyE Cyclophosphamide/(50 mg/kg)/IV -3 and -2 Cyclophosphamide* High ASCO MASCC/ESMO NCCN Etoposide/400/IV -5 and -4 Etoposide**

Overview Solid tumors Hematological malignancies Days of Emetogenic Antiemetic prophylaxis Regimen 2 administration potential of single Emetic risk Ref. N. Agent/dose (mg/m )/route including NK1 RA (reference) (day 0: stem cells agents of the regimen§ recommendation by infusion) (descending order) Busulphan/(0.8 mg/kg; q 6 hrs)/IV -7 to -5 Busulphan* 112 BuCyVP Cyclophosphamide/(60mg/kg)/civ -3 to -2 Cyclophosphamide* High ASCO MASCC/ESMO NCCN Etoposide/60mg/kg)/civ -3 to -2 Etoposide** Fotemustine/150/IV -7 and -6 or Fotemustine* 113, Fotemustine/300/IV -6 Melphalan** FEAM High ASCO MASCC/ESMO NCCN 114 Etoposide/200/IV -5 to -2 Cytarabine** Cytarabine/400/IV -5 to -2 Etoposide** Melphalan/140/IV -1 115, Melphalan/70-100/IV -1 and -2 Hi-MEL High-dose melphalan High ASCO MASCC/ESMO NCCN 116 Mitoxantrone/60/IV -5 Mitoxantrone* 117 Mito-MEL High ASCO MASCC/ESMO NCCN Melphalan/180/IV -2 Melphalan** Thiotepa/300/IV -8 and -7 Thiotepa* 118 TBC Busulphan/(9.6 mg/kg)/IV -6 to -4 Busulphan* High ASCO MASCC/ESMO NCCN Cyclophosphamide/2000/IV -3 to -2 Cyclophosphamide** Thiotepa/250/IV -9 to -7 Thiotepa* 119, TBC Busulphan/(8 mg/kg)/IV -6 to -4 Busulphan* High ASCO MASCC/ESMO NCCN 120 Cyclophosphamide/(60 mg/kg)/IV -3 and -2 Cyclophosphamide** Thiotepa/166/IV -6 to -4 Thiotepa* 121 TEC Etoposide/250/IV -7 to -4 Etoposide** High ASCO MASCC/ESMO NCCN Carboplatin/266/IV -6 to -4 Carboplatin**

* High emetic risk as a single agent at the indicated dose level. ** Moderate emetic risk as a single agent at the indicated dose level. § Patients receiving multi-day chemotherapy are at risk for both acute and delayed nausea and emesis based upon the emetogenic potential of the individual agents and their sequence. References 1. Buzzoni R, Buonadonna G, Valagussa P, et al. comparative trial of adriamycin versus methotrexate alone or with bevacizumab for non-small cell lung Adjuvant chemotherapy with doxorubicin plus in combination drug therapy. Cancer 1978; cancer. N Engl J Med 2006; 355:2542-2550 cyclophosphamide, methotrexate, and fluorouracil in 41:1649-1657 16. Robert N, Leyland-Jones B, Asmar L, et al. Randomized the treatment of resectable breast cancer with more 9. Cassidy J, Clarke S, Diaz Rubio E, et al. Randomized phase III study of trastuzumab, paclitaxel, than three positive axillary nodes. 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A single centre analysis on toxicity and 172(1):111-21. doi: 10.1111/bjh.13803. Epub 2015 efficacy. Leuk Lymphoma 2003; 44: 1151–1158 Oct 12 Busulfan, and Cyclophosphamide (TBC) Conditioning 105. Mills W, Chopra R, McMillan A, et al. BEAM 113. Dean RM, Pohlman B, Sweetenham JW, et al. Superior in Patients with CNS Involvement by Non-Hodgkin chemotherapy and autologous bone marrow survival after replacing oral with intravenous busulfan Lymphoma. Biol Blood Marrow Transplant 2012; 18: transplantation for patients with relapsed or refractory in autologous stem cell transplantation for non- 76-83 non-Hodgkin’s lymphoma. J Clin Oncol 1995; 13: Hodgkin lymphoma with busulfan, cyclophosphamide 121. Falzetti F, Ianni MD, Ballanti S, et al. High-dose thiotepa, 588–595 and etoposide. Br J Haematol 2010; 148:226-34 etoposide and carboplatin as conditioning regimen for 106. Visani G, Malerba L, Stefani PM, et al. BeEAM 114. Musso M, Scalone R, Marcacci G, et al. Fotemustine autologous stem cell transplantation in patients with (bendamustine, etoposide, cytarabine, melphalan) plus etoposide, cytarabine and melphalan (FEAM) as high-risk non-Hodgkin lymphoma. Clin Exp Med 2011 before autologous stem cell transplantation is safe a new conditioning regimen for lymphoma patients Sep 18 [Epub ahead of print] DISCLAIMER This pocket guide is a summary of cancer therapeutic agents and regimens and of their emetogenicity according to the available evidence and guidelines. Although detailed, this pocket guide is not intended or designed as an exhaustive review and should not be considered a tool for the choice of the chemotherapy regimen. No liability will be assumed by Helsinn Healthcare SA for the use of this pocket guide and the absence of errors, omissions, or inaccuracies is not guaranteed. For detailed information on single agents, regimens, dosages, and indications, the reader is invited to consult drugs’ prescribing information as well as international literature and guidelines.

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MAT − MASCC Antiemesis Tool HHC-CINV-008-DEC19