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: