Clinical and Translational Oncology (2022) 24:712–723 https://doi.org/10.1007/s12094-022-02802-1 CLINICAL GUIDES IN ONCOLOGY SEOM Clinical Guideline update for the prevention of chemotherapy‑induced nausea and vomiting (2021) Margarita Majem1 · Ramon de las Peñas2 · Juan Antonio Virizuela3 · Luís Cabezón‑Gutiérrez4 · Patricia Cruz5 · Rafael Lopez‑Castro6 · Miriam Méndez7 · Rebeca Mondéjar8 · María del Mar Muñoz9 · Yolanda Escobar10 Accepted: 26 January 2022 / Published online: 26 March 2022 © The Author(s) 2022, corrected publication 2022 Abstract Among the side effects of anticancer treatment, chemotherapy-induced nausea and vomiting (CINV) is one of the most feared given its high prevalence, affecting up to 40% of patients. It can impair patient’s quality of life and provoke low adherence to cancer treatment or chemotherapy dose reductions that can comprise treatment efficacy. Suffering CINV depends on factors related to the intrinsic emetogenicity of antineoplastic drugs and on patient characteristics. CINV can appear at different times regarding the administration of antitumor treatment and the variability of risk according to the different antitumor regimens has, as a consequence, the need for a different and adapted antiemetic treatment prophylaxis to achieve the desired objective of complete protection of the patient in the acute phase, in the late phase and in the global phase of emesis. As a basis for the recommendations, the level of emetogenicity of anticancer treatment is considered and they are classified as high, moderate, low and minimal emetogenicity and these recommendations are based on the use of antiemetic drugs with a high therapeutic index: anti 5-HT, anti-NK and steroids. Despite having highly effective treatments, clinical reality shows that they are not applied enough, so evidence-based recommendations are needed to show the best options and help in decision-making. To cover all the antiemetic prophylaxis options, we have also included recommendations for oral treatments, multiday regimens and radiation-induced emesis prevention. Keywords Emesis · Nausea · Vomiting · Chemotherapy 1 * Margarita Majem Department of Medical Oncology, Hospital de la Santa MMajem@santpau.cat Creu i Sant Pau, c/Sant Antoni Maria Claret 167, 08025 Barcelona, Spain Ramon de las Peñas 2 ramon.delaspenas1956@gmail.com Department of Medical Oncology, Hospital Provincial Castelló, Valencia, Spain Juan Antonio Virizuela 3 javirizuelae@seom.org Department of Medical Oncology, Hospital Universitario Virgen Macarena, Seville, Spain Luís Cabezón‑Gutiérrez 4 pitucgp@hotmail.com Department of Medical Oncology, Hospital Universitario de Torrejón, Madrid, Spain Patricia Cruz 5 patriciacruzcastellanos@gmail.com Department of Medical Oncology, Hospital Universitario La Paz, Madrid, Spain Rafael Lopez‑Castro 6 rafalopezcastro@yahoo.es Department of Medical Oncology, Hospital Clínico Universitario de Valladolid, Valladolid, Spain Miriam Méndez 7 mirimega@hotmail.com Department of Medical Oncology, Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, Spain Rebeca Mondéjar 8 rmondejars@hotmail.com Department of Medical Oncology, Hospital Universitario de La Princesa, Madrid, Spain María del Mar Muñoz 9 mmmunozs@yahoo.es Department of Medical Oncology, Hospital Virgen de la Luz de Cuenca, Cuenca, Spain Yolanda Escobar 10 yolandaesco@yahoo.es Department of Medical Oncology, Hospital General Universitario Gregorio Marañón, Madrid, Spain 13 Vol:.(1234567890) Clinical and Translational Oncology (2022) 24:712–723 713 Introduction Guideline methods Among the side effects of anticancer treatment, chemother- The authors have reviewed the published clinical guidelines, apy-induced nausea and vomiting (CINV) is one of the most as well as clinical trials from which the aspects referred to feared by patients given its high prevalence, affecting up to in these guidelines can be concluded. 40% of patients [1]. It can impair patient’s quality of life [2], Each author has been responsible for reviewing a part of and also provoke low adherence to cancer treatment [3] or the guideline that has been shared and discussed among all the chemotherapy dose reductions that can compromise treat- authors to reach a consensus. Finally, the degrees of evidence ment efficacy [4]. and recommendation have been established based on the rec- The likelihood of suffering from CINV weighs down, on ommendations for the development of guidelines [14, 15]. one hand, on patient conditioning factors and, on the other hand, on intrinsic cancer drug properties. Some patient characteristics are linked with higher Types of chemotherapy‑induced nausea emesis related with cancer treatment: low performance and/or vomiting (CINV) status, younger age, female gender, unusual alcohol intake, hyperemesis gravidarum and motion sickness; also, medical CINV is also known as emesis, although nausea and vomit- conditions such as previous CINV, anxiety, metabolic dis- ing can occur independently due to their different pathophys- orders (dehydration, hyperkalemia, hypocalcemia, hypona- iology [16, 17]. CINV is commonly classified into the fol- tremia), ascites, bowel obstruction, and use of concurrent lowing five types: acute, delayed, anticipatory, breakthrough, drugs (opioids, antibiotics…) can increase this risk [5–7]. and refractory [18]. There can also be a genetic predisposition through poly- Acute CINV occurs in the first 24h after chemotherapy morphisms of the enzymes that metabolize 5-HT3 receptor and its intensity peaks occur after 5–6h. In acute CINV, antagonists and of the receptor itself that increases emesis free radicals generated by chemotherapy stimulate cells in probabilities [8]. the gastrointestinal tract, which release serotonin (5-HT3). Regarding cancer drugs, their own characteristics and The activation of the 5-HT3 receptors triggers the vomiting risk of CINV have led to classify them into four groups reflex and chemoreceptor trigger zone in the central nervous regarding their probability of emesis: highly, moderately, system [19]. low- and minimallyemetogenic drugs; their combination in Delayed CINV occurs later than 24h after chemotherapy polychemotherapy regimens also increases the risk (Tables 1 administration, typically between 48 and 72h and is medi- and 2) [9]. ated primarily by substance P; the action of substance P is It is crucial to identify these factors when planning a can- mediated by NK1 receptor that affects sensory and noci- cer treatment strategy, given the high importance of avoiding ceptive pathways and inflammation [5, 20]. It commonly CINV to achieve treatment goals and preserving patient’s occurs with administration of highly emetic chemotherapy; quality of life. Various cancer scientific societies have devel- for cisplatin, delayed CINV can persist for 5–6days. oped and published guidelines on antiemetic therapy [5, Anticipatory CINV occurs before receiving the next 10–12] to provide tools to face the different risk scenarios- chemotherapy cycle. It is attributed to a previous adverse with the best prophylaxis of CINV. CINV experience, so it is considered a conditioned response. Any cancer treatment should follow several principles for Incidence of anticipatory CINV ranges from 10 to 45%, and theprevention in CINV [13]: nausea is more common than vomiting. Significant predic- tive factors include younger age (< 50years), female gender • Prophylaxis is the primary goal of antiemetic therapy. and susceptibility to motion sickness [21, 22]. • Any patient or treatment with an emetic risk greater than Breakthrough CINV occurs within 5days of the end of 10% should receive adequate prophylaxis. chemotherapy despite the use of adequate prophylactic • Antiemetic therapy should cover the entire risk period. antiemetic agents. This type of CINV usually requires res- • Oral or intravenous routes for antiemetic drugs offer the cue therapy with additional antiemetic treatment. Approxi- same efficacy. mately 30–40% of patients receiving moderate or highly • Selection of antiemetic therapy must be based on chemo- emetic chemotherapy can have breakthrough CINV and they therapy emetogenicity, plus patient’s risk factors. should be considered for a higher level of prophylaxis during subsequent cycles of chemotherapy [22, 23]. 13 714 Clinical and Translational Oncology (2022) 24:712–723 Table 1  Emetogenic potential of parenteral anticancer agents Level Agent High emetic risk AC combination defiend as any Cisplatin Meclorethamine (> 90% frecuency of chemotherapy regimen that Cyclophosphamide> Melphalan ≥ 140mg/m² emesis) contains an antracyclinne and 1500mg/m² Sacituzumab govitecan- cyclophosphamide Dacarbazine hziy Carboplatin AUC ≥4 Doxorubicine ≥60mg/m² Streptozocin Carmustine > 250mg/m² Epirubicin> 90mg/m² Ifosfamide ≥2g/m² per dose Moderate emetic risk Aldesleukin > 12–15million IU/m² Daunorubicin Lurbinectedin (> (30–90% frecuency of Amifostine > 300mg/m² Dual-drug liposomal encap- Melphalan <140mg/m² emesis) Amivantamab sulation of cytarabine and Methotrexate ≥ 250mg/m² Azacitidine daunorubicin Naxitamab-gqgk Bendamustine Dinutuximab Oxaliplatin Busulfán Doxorubicin <60mg/m² Temozolomide Carboplatino AUC <4 Epirubicin ≤90mg m² Trabectedin Carmustine ≤250mg/m² Fam-trastuzumab deruxte- Clofarabine can-nxki Cyclophosfamide ≤ 1500mg/m² Idarubicin Cytarabine> 200mg m² Ifosfamide <2g(m² per dose Dactinomicine Irinotecan Irinotecan (liposomal) Low emetic risk Ado-trastuzumab emtansine Docetaxel Methotrexate > 50mg/m² < Pralatrexatee (10–30% frecuency of Aldesleukin ≤12million IU/m² Doxorubicin (liposomal) 250mg/m² Tafasitamab-cxix emesis) Amifostine < 300mg/m² Enfortumab vedotin-ejv Mitomycin Tagraxofusp-erzs Arsenic trioxide Eribulin Mitomycine pyelocaelyceal Talimogene laher- Axicabtagene ciloleucel Etopóside solution parepvec Belinostat 5-fluorouracil (5-FU) Mitoxantrone Thiotepa Brexucabtagene autoleucel Floxuridine Mogamulizumab-kpkc Tisagenlecleucel Brentuximab vedotin Gemcitabine Moxetumomab pasudotox- Tisotumab ven- Cabazitaxel Gemtuzumab ozogamicin tdfk dotin- Carfilzomib Idecabtagene vicleucel Necitumumab Topotecán Cytarabine (low dose)100–200mg/ Inotuzumab ozogamicina Omacetaxine Ziv-aflibercept m² Isatuximab-irfc Paclitaxel Ixabepilone Paclitaxel-albumin lisocabtagene maraleucel Pemetrexed Loncastuximab terisine-lpyl Pentostatina Polatuzumab vedotin Minimal emetic risk Alemtuzumab Daratumumab and hyaluro- Obinutuzumab Siltuximab (<10% frecuency of Asparaginase nidase-fihj Ofatumumab Temsirolimus emesis) Atezolizumab Decitabine Panitumumab Trastuzumab Avelumab Denileukin diftitox Pembrolizumab Trastuzumab and belantamab mafodotin-blmf Dostarlimab-gxly Pertuzumab hyaluronidase- Bevacizumab Dexrazoxane Pertuzumab / trastuzumab oysk Bleomycin Durvalumab and hyaluronidase-zzxf Valrubicin Blinatumomab Elotuzumab Ramucirumab Vinblastine Bortezomib Fludarabine Rituximab Vincristine Cetuximab Ipilimumab Rituximab and hyaluroni- Vincristine (lipo- Cemiplimab-rwlc Luspatercept-aamt dase somal) Cladribine Margetuximab-cmkb Vinorelbine Cytarabine <100mg/m² Methotrexate ≤50mg/m² Daratumumab Nelarabine Nivolumab Based in NCCN clinical practice guidelines in oncology (NCCN ­Guidelines®) Antiemesis Version 1.2022 13 Table 2  Emetogenic potential of oral anticancer agents Level Agent Moderate to high emetic risk Altretamine Crizotinib Etoposide Niraparib (≥30% frecuency of emesis) Avapritinib Cyclophosfamide ≥100 mg/m²/day Fedratinib Olaparib Azacytidine Dabrafenib Imatinib> 400mg/day Procarbazine Binimetinib Enasidenib Lenvatinib> 12mg/day Rucaparib Bosutinib > 400mg/day Encorafenib Lomustine (single day) Selinexor Busulfan ≥ 4mg/day Estramustine Midostaurin Temozolomide > 75mg/m²/day Cabozantinib Mitotane Clinical and Translational Oncology (2022) 24:712–723 Ceritinib Mobocertinib Minimal to low emetic risk Abemaciclib Duvelisib Lorlatinib Sonidegib (<30% frecuency of emesis) Acalabrutinib Entrectinib Melphalan Sorafenib Afatinib Erdafitinib Mercaptopurine Sotorasib Alectinib Erlotinib Methotrexate Sunitinib Alpelisib Everolimus Nilotinib Talazoparib tosylate Asciminib Fludarabine Neratinib Tazemetostat Axitinib Gefitinib Osimertinib Temozolomide ≤75mg/m²/day Belzutifan Gilteritinib Palbociclib Tepotinib Bexarotene Glasdegib Pazopanib Thalidomide Brigatinib Hydroxyurea Pemigatinib Thioguanine Bosutinib ≤ 400mg/day Ibrutinib Pexidartinib Tivozanib Busulfan <4mg/day Idelalisib Pomalidomide Topotecán Capecitabine Imatinib ≤ 400mg/day Ponatinib Trametinib Capmatinib Ixazomib Pralsetinib Tretinoin Chlorambucil Ivosidenib Regorafenib Trifluridine/tipiracil Cobimetinib Lapatinib Ribociclib Tucatinib Cyclophosfamide <100mg/m²/day Larotrectinib Ripretinib Umbralisib Dacomitinib Lenalidomide Ruxolitinib Vandetanib Dasatinib Lenvatinib ≤12mg/day Selpercatinib Vemurafenib Decitabine and cedazuridine Venetoclax Vismodegib Vorinostat Zanubrutinib Based in NCCN clinical practice guidelines in oncology (NCCN ­Guidelines®) Antiemesis Version 1.2022 13 715 716 Clinical and Translational Oncology (2022) 24:712–723 Refractory CINV occurs in subsequent chemotherapy Other drugs such as benzodiazepines or cannabinoids cycles despite the use of adequate antiemetic prophylaxis have a different mechanism of action, and their use is contro- and rescue therapy. versial, generally relegated to delayed, anticipatory emesis or in the rescue treatment (Level of Evidence II, Grade of Recommendation C). Overview and pharmacologic considerations The combination of the different drugs, as stated in the guidelines, allows for antiemetic therapy to be adapted to The pathophysiology of CINV involves the participation each patient and clinical situation. of various areas of the nervous system, as well as afferent and efferent pathways that will be responsible for emesis. Antiemetic drugs exert their action by acting on the recep- Emesis prevention for high emetic risk IV tors of the different neurotransmitters responsible for chem- anticancer drugs (Table 3) otherapy-induced emesis [24]. The dopamine D2 receptor antagonists (D2-RAs) include Highly emetic chemotherapy (HEC) includes those agents or phenothiazine (proclorpromacine, perphenazine, and tietilp- schedules that would cause emesis in more than 90% of the eracilin), butyrophenones, (haloperidol and droperidol) and cases in the absence of antiemetic prophylaxis [24]. substituted benzamides (metoclopramide, domperidone, HEC prophylaxis consists in administering a three-drug and alizapride). Currently, its use is relegated to refractory regimen including 5HT3-RAs, NK1-RAs and steroids (Level emesis or when modern agents or steroids are contraindi- of Evidence I, Grade of Recommendation A) [2, 3]. Palono- cated (Level of Evidence V, Grade of Recommendation B). setron is the preferred 5HT3-RA because of its superiority in The serotonin receptor antagonists (5-HT3-RAs) include controlling delayed emesis [29]. The addition of olanzapine first-generation agents—ondansetron, granisetron, dola- to the triplet should be considered when the occurrence of setron, tropisetron, and second-generation agents—palo- nausea associated with HEC is an issue. (Level of Evidence nosetron. Palonosetron has demonstrated greater efficacy I, Grade of Recommendation A). Data suggest that a 5mg than first-generation agents, as it produces a long-lasting dose of olanzapine is efficacious; this dose is recommended serotonin receptor blockade and has synergistic activity with especially for elderly or oversedated patients [27, 30]. neurokinin inhibitors (Level of Evidence I, Grade of Rec- Efficacy of the three-drug antiemetic regimen olanzapine ommendation A). Administration of these drugs days after plus palonosetron plus dexamethasone did not differ signifi- chemotherapy is not recommended because it has not proven cantly in terms of complete response rates to aprepitant plus to be beneficial, and they have associated side effects. palonosetron plus dexamethasone. (Level of Evidence IB, The neurokinin-1 receptor antagonists (NK1-RAs) Grade of Recommendation A) [4]. include aprepitant, fosaprepitant, and netupitant. Netupitant Current data indicate that the dexamethasone doses is a second-generation NK1-RA that targets the serotonin may be individualized. High doses may be considered for and substance P-mediated pathways involved predominantly no-NK1 regimens. Low doses or with shorter duration can in delayed emesis. Oral netupitant is combined with oral be planned for non-cisplatin regimens based on patient char- palonosetron (NEPA) in a single tablet [25, 26]. In combi- acteristics. (Level of evidence 2, Grade of Recommendation nation with 5-HT3-RAs and steroids, NK1-RAs offer better A) [11, 12]. control in acute and delayed emesis in highly emetic chemo- therapy regimens (Level of Evidence I, Grade of Recom- mendation A). Emesis prevention for moderate emetic risk Olanzapine is a second-generation antipsychotic agent IV anticancer drugs (Table 3) that blocks serotonin 5-hydroxytryptamine (5-HT2) recep- tors and dopamine D2 receptors. A four-drug antiemetic Moderately emetic chemotherapy (MEC) includes those regimen adding olanzapine is effective for preventing CINV with an associated risk of CINV between 30 and 90%. The in high emetic chemotherapy and moderate emetic chemo- combination of a 5-HT3-RA and dexamethasone is the pre- therapy schedules (Level of evidence I, Grade of Recom- ferred option for the prevention of acute emesis [5, 11, 18]. mendation A) [27]. The 5-HT3-RA of choice is palonosetron [31]. (Level of Current data indicate that dexamethasone doses may be Evidence II, Grade of Recommendation B). There are other individualized. High doses may be considered for non-NK1- alternatives to prevent acute emesis in MEC, such as the RAs-containing regimens. Lower doses or shorter duration addition of a NK1-RA to 5-HT3-RA and dexamethasone or (“dexa sparing” schedules) can be used for non-cisplatin the combination of olanzapine, palonosetron and dexametha- regimens based on patient characteristics (Level of Evidence sone. (Level of Evidence II, Grade of Recommendation B). I, Grade of Recommendation A) [28]. 13 Clinical and Translational Oncology (2022) 24:712–723 717 Table 3  Emesis prevention recommendations for high, moderate, low and minimal emetic risk IV anticancer drugs ASCO guidelines NCCN guidelines MASCC/ESMO guidelines Emesis prevention for high emetic risk IV anticancer drugs ACUTE Single dose of NK1-RA (choose one): OPTION A (PREFERRED) Single dose of NK1-RA (choose one) : Day 1 (start Aprepitant 125 mg oral or 130 IV Olanzapine 5–10 mg PO once Aprepitant 125 mg oral before Fosaprepitant 150 mg IV Single dose of NK1-RA (choose one): Fosaprepitant 150 mg IV anticancer Netupitant-palonosetron 300 mg Aprepitant 125 mg oral Netupitant-palonosetron 300 mg treatment) netupitant/0.5 mg palonosetron oral Fosaprepitant 150 mg IV netupitant/0.5 mg palonosetron oral in single capsule Netupitant-palonosetron 300 mg netupi- in single capsule Single dose of 5-HT3-RA (choose tant/0.5 mg palonosetron oral in single Single dose of 5-HT3-RA (choose one): capsule one): Granisetron 2 mg PO / 1 mg IV once Single dose of 5-HT3-RA (choose one): Granisetron 2 mg PO / 1 mg IV once Ondansetron 8 mg PO or IV once Granisetron 2 mg PO / 1 mg IV once Ondansetron 8 mg PO or IV once Palonosetron 0.25 mg IV Ondansetron 8–16 mg PO or 16–24 IV once Palonosetron 0.25 mg iIV Dexamethasone 12 mg PO/IV Palonosetron 0.25 mg IV Dexamethasone 12 mg once Olanzapine 5-10 mg PO Dexamethasone 12 PO/IV Olanzapine 5–10 mg PO when nausea OPTION B is an issue Palonosetron 0,25 mg IV once Dexamethasone 12 mg PO/IV Olanzapine 5-10 mg PO once OPTION C Single dose of NK1-RA (choose one): Aprepitant 125 mg oral Fosaprepitant 150 mg IV Netupitant-palonosetron 300 mg netupi- tant/0.5 mg palonosetron oral in single capsule Single dose of 5-HT3-RA (choose one): Granisetron 2 mg PO / 1 mg IV once Ondansetron 8–16 mg PO or 16–24 IV once Palonosetron 0.25 mg IV Dexamethasone 12 mg PO/IV once DELAYED Aprepitant 80 mg PO on days 2–3 (if OPTION A Aprepitant 80 mg PO on days 2-3 (if Days 2–4 aprepitant PO on day 1) Olanzapine 5-10 mg PO daily on days 2-4 aprepitant PO on day 1) Dexamethasone 8 mg oral or IV once Aprepitant 80 mg PO daily on days 2,3 ( if Dexamethasone 8 mg once daily (*) daily on days 2-4 (*) aprepitant PO on day 1) Olanzapine 5–10 mg PO when nausea Olanzapine 5–10 mg oral on days 2–4 Dexamethasone 8 mg PO/IV once daily is an issue OPTION B Olanzapine 5-10 mg PO daily on days 2-4 OPTION C Aprepitant 80 mg PO daily on days 2,3 (if aprepitant PO on day 1) Dexamethasone 8 mg PO/IV daily on days 2-4 Emesis prevention for moderate emetic risk IV anticancer drugs ACUTE Dexamethasone 8 mg PO/IV once Dexamethasone 12 PO/IV once Dexamethasone 8 mg PO/IV once Day 1 (start Single dose of 5-HT3-RA (choose Single dose of 5-HT3-RA (choose one): Single dose of 5-HT3-RA (choose before one): Granisetron 2 mg PO once or 1 mg IV one): anticancer Ondansetron 8 mg PO twice daily or 8 Ondansetron 16-24 mg PO once or 8-16 IV Granisetron 2 mg PO once or 1 mg IV treatment) mg IV daily once Ondansetron 16–24 mg PO once or Palonosetron 0.25 mg iIV Palonosetron 0.25 mg IV once (preferred) 8-16 IV once +/− Palonosetron 0.25 mg IV once Single dose of NK1-RA (choose one) Aprepitant 125 mg PO once Fosaprepitant 150 mg IV once or Netupitant 300 mg/Palonsetron 0.5 mg PO once ALTERNATIVE TREATMENT Olanzapine 5–10 mg PO once Palonosetron 0.25 mg IV once Dexametasone 12 mg PO/IV once 13 718 Clinical and Translational Oncology (2022) 24:712–723 Table 3  (continued) ASCO guidelines NCCN guidelines MASCC/ESMO guidelines DELAYED No prophylaxis Dexamethasone 8 PO/IV once No prophylaxis Days 2-3 or or or Dexamethasone 8 mg PO or IV (**) 5-HT3-RA: Dexamethasone 8 mg PO or IV daily Granisetron 1–2 mg PO daily or 1 mg IV (**) daily Ondansetron 8 mg PO twice daily or 16 mg PO daily or 8-16 mg IV daily OR Aprepitant 80 mg on days 2-3 (if oral aprepi- tant on day 1) PO +/- Dexamethasone 8 mg PO or IV daily on days 2 and 3 OR ALTERNATIVE TREATMENT Olanzapine 5-10 mg PO days 2-3 Emesis prevention for low emetic risk IV anticancer drugs ACUTE Single dose of 5-HT3-RA (choose Dexamethasone 8-12 PO/IV once Dexamethasone 4–8 mg once Day 1 (start one): OR OR before Granisetron 2 mg PO or 1 IV once Metoclopramide 10-20 mg PO/IV once Single dose of 5-HT3-RA (choose anticancer Granisetron 2 mg PO / 1 mg IV once OR one): treatment) Palonosetron 0.25 mg iIV Prochlorperazine 10 mg PO/IV once Ondansetron IV 8 mg or 8-16 mg PO OR OR Granisetron 1mg IV-PO or 2 mg PO Dexamethasone 8 mg PO/IV 5-HT3-RA (choose one): Palonosetron 0.25 IV Granisetron 1–2 mg (total dose) PO once OR Ondansetron 8–16 mg PO once Metoclopramide 10–20 mg PO/IV once DELAYED No routine prophylaxis No routine prophylaxis No routine prophylaxis Emesis prevention for minimal emetic risk IV anticancer drugs ACUTE No routine prophylaxis No routine prophylaxis No routine prophylaxis Day 1 DELAYED No routine prophylaxis No routine prophylaxis No routine prophylaxis (*)Not recommended in Anthracycline combined with cyclophosphamide (**)For agents known to cause delayed emesis (oxaliplatin, ciclofosfamide and doxorubicine) To prevent carboplatin-induced acute emesis, a combi- Emesis prevention for low and minimal nation of an NK1-RA, 5-HT3-RA and dexamethasone is emetic risk IV anticancer drugs (Table 3) recommended (Level of Evidence II, Grade of Recommen- dation B) [32]. Drugs with low emetic potential are those for which the Prophylactic treatment against delayed CINV is not risk of CINV lies between 10 and 30%. For drugs having routinely recommended in patients receiving MEC except a minimal emetogenic potential, the risk is < 10%. Most with those therapies that are more frequently associated new targeted agents and immune-checkpoint inhibitors are with the onset of delayed CINV (for example, oxaliplatin, included in this category. The optimal treatment to prevent anthracyclines or cyclophosphamide). In these cases, it acute CINV in patients receiving low emetic risk antican- is recommended to add dexamethasone on days 2 and 3. cer drugs (CT) includes a single antiemetic agent adminis- Other alternatives are the use of olanzapine or 5-HT3-RA tered before treatment such as 5-HT3-RA, dexamethasone on days 2 and 3 (Level of evidence II; Grade of Recom- or D2-RAs, (i.e., metoclopramide) (Level of Evidence II, mendation B). Grade of Recommendation B) [5]. The use of antiemetic prophylaxis against delayed CINV for low emetogenic CT is not recommended (Level of Evidence II, Grade of Recom- mendation B) [11]. 13 Clinical and Translational Oncology (2022) 24:712–723 719 No antiemetic treatment should be routinely administered [24]. Numerous new oral antineoplastic agents have been before or after minimally emetogenic antineoplastic agents introduced in NCCN and MASCC/ESMO antiemetic guide- in patients without a history of nausea and vomiting. (Level line update that must be incorporated into the emetogenic of Evidence IV, Grade of Recommendation D). If a patient classification [11, 18]. experiences acute or delayed nausea or vomiting after low or Oral antiemetic prophylaxis is recommended for highly or minimally emetogenic drug, prophylactic antiemetic treat- moderately emetogenic oral agents. Single-agent antiemetic ment might be considered for subsequent chemotherapy therapy with 5HT3-RA should be started before anticancer administrations using the regimen for the next higher emetic therapy and continue daily for the duration of the treatment level (Level of Evidence II, Grade of Recommendation B) (Level of Evidence II, Grade of Recommendation B) [18, [9, 18]. 34]. Recommended prophylaxis in patients receiving low- or minimal-emetogenic oral agents with a single antiemetic Emesis prevention for multiday IV oral agent like a D2-RA (metoclopramide, prochlorpera- chemotherapy zine) or a 5HT3-RA is recommended in case of appearance of CINV. Level of Evidence II, Grade of Recommendation Prophylaxis of CINV in patients receiving moderately or B). If multiple oral agents are combined, emetic risk may highly emetic multiday chemotherapy is more difficult, due increase and require adequate prophylaxis. to a mixture of acute and delayed effects, as well as anticipa- tory emesis [18]. Practical issues should be considered (i.e., route of administration, administration setting or duration Breakthrough emesis and rescue antiemetic of action of 5-HT3-RA, dosing intervals, compliance issues therapy or individual risk factors). Moreover, there are few clinical studies that look at this situation [11]. Breakthrough nausea and vomiting and rescue antiemetic Patients receiving moderately or highly emetic multiday therapy is a challenging situation. Other causes for eme- chemotherapy should receive a 5-HT3-RA plus dexametha- sis (i.e., use of opioid medication, central nervous system sone for acute emesis and dexamethasone for delayed emesis metastases, hypercalcemia, or gastrointestinal obstruc- (Level of Evidence II, Grade of Recommendation A). Dexa- tion) must be ruled out. There are no data from specifically methasone should be administered once daily in the morning designed clinical trials in this area (Level of Evidence V, and maintained 2–3days after chemotherapy for regimens Grade of Recommendation C), but the following recommen- likely to cause significant delayed emesis [11]. NK1-RA dations can be followed [35, 36]: may also be used in those regimens associated with signifi- cant risk of delayed emesis. If the regimen does not contain • Patients must have received appropriate antiemetic treat- an NK1-RA, palonosetron is the preferred 5-HT3-RA [33]. ment (Level of Evidence I, Grade of Recommendation For patients with moderately emetic multiday chemotherapy, A). limiting the administration of dexamethasone to day 1 is an • There is evidence to suggest that refractory emesis may option (especially in intolerant to corticosteroids patients) respond to a switch from one 5-HT3-RA to another that may not be associated with a significant efficacy reduc- (Level of Evidence II, Grade of Recommendation C). tion [11]. If patients cannot tolerate dexamethasone, con- • After a course refractory to antiemetic treatment, an sider replacing with olanzapine. attempt can be made to adjust the scheme for the next cycle to a higher risk group (Level of Evidence V, Grade of Recommendation C). Emesis prevention for oral anticancer drugs • If the patient received an oral regimen, the physician could consider giving agents intravenously, although Separate classifications have been established for intrave- there is no evidence that this will improve efficacy (Level nous and oral antineoplastic agents (oral agents are usually of Evidence V, Grade of Recommendation C). given daily and over longer periods). This classification has • As rescue therapy, a drug with a different mechanism of some limitations: categorical data on the intrinsic emetic action can be used (i.e. lorazepam, alprazolam, olanzap- risk are available for only few agents, the classification ine, prochlorperazine, or haloperidol) (Level of Evidence underestimates the risk of delayed emesis and of acute and V, Grade of Recommendation C). Olanzapine has shown delayed nausea, and the classification does not address the superiority over metroclopramide in a recent randomized emetogenic potential of combination regimens, which is usu- trial (Level of Evidence II, Grade of Recommendation ally determined by the most emetic agent of the combination B). 13 720 Clinical and Translational Oncology (2022) 24:712–723 Anticipatory emesis prevention Concurrent chemoradiotherapy‑induced and treatment emesis prevention The best way to prevent anticipatory nausea and vomit- In patients receiving concurrent chemoradiotherapy, it is ing is to achieve good control of acute and delayed emesis advised to prescribe antiemetics according to the emetogenic (Level of evidence III; Recommendation grade B) [37, potential of the chemotherapy unless it is considered that the 38]. Benzodiazepines may help in the treatment of antici- risk of nausea and vomiting induced by the radiotherapy is patory nausea, as they help reduce the anxiety associated higher. with chemotherapy administration and the most studied During periods when prophylactic antiemetic therapy for therapy is lorazepam [39, 40]. The recommended regimen chemotherapy has ended and ongoing radiotherapy contin- of lorazepam is to start at doses of 0.5–2mg the night before ues, patients should receive prophylactic therapy appropriate antitumor treatment and repeating the dose 1 or 2h before for the emetogenic risk of the radiotherapy until the next administration (Level of evidence II; Grade of Recommen- course of chemotherapy, rather than receiving breakthrough dation A). Other therapies such as acupuncture [41, 42] have therapy (Level of Evidence II, Grade of recommendation been shown to be effective in controlling anticipatory emesis A) [45, 46]. (Evidence level II; Recommendation grade B). Behavioral interventions, such as progressive muscle relaxation and systematic desensitization training, should be considered Summary of recommendations effective methods for the prevention and treatment of this type of emesis (Evidence level II, Recommendation grade B) [43, 44]. Principles of prevention in Prophylaxis is the primary goal of CINV antiemetic therapy Any patient receiving treatment Radiation induced emesis prevention with an emetic risk greater than 10% should receive adequate Radiation-induced emesis (RINV) is divided into four risk prophylaxis levels: high, moderate, low, and minimal. These levels Antiemetic therapy should cover the entire risk period depend on the site of radiation and do not consider radia- Oral or intravenous routes for tion dose, fractionation, technique or other proposed risk antiemetic drugs offer the same factors [5]. efficacy Patients on highly emetogenic radiotherapy (total body Selection of antiemetic therapy must be based on chemotherapy irradiation) should receive an oral 5-TH3-RA ± dexametha- emetogenicity and patient’s risk sone each day of radiotherapy treatment. (Level of Evidence factors II, Grade of Recommendation B). Emesis prevention in high HEC prophylaxis consists in a Subjects receiving moderately emetic radiotherapy (upper emetic risk IV anticancer three-drug regimen includ- abdomen, craniospinal locations) should receive an oral drugs ing 5-HT3-RAs, NK1-RA and steroids 5-HT3-RA each day of treatment and optional short-course Palonosetron is the preferred of oral dexamethasone (Level of Evidence II, Grade of rec- 5HT3-RA ommendation A) [11]. The addition of olanzapine should Those who are receiving low emetic radiotherapy (tho- be considered when the occur- rence of nausea is an issue rax, cranium, head and neck, and pelvis) should receive A three-drug antiemetic regimen prophylaxis or rescue with one of the following drugs: an with olanzapine, palonose- oral 5-HT3-RA, dexamethasone (preferred in SNC RT), or tron and dexamethasone is an a D2-RA (Level of Evidence IV, Grade of Recommendation alternative D) [9]. Patients receiving minimally emetic radiotherapy (extremities, breast) should not receive antiemetics routinely, but breakthrough treatment with a D2-RA or a 5-HT3-RA may be prescribed if patient presents radiation-induced emesis (Level of Evidence IV, Grade of Recommendation D) [18]. 13 Clinical and Translational Oncology (2022) 24:712–723 721 Emesis prevention in moder- A combination of 5-HT3-RA and Anticipatory emesis prevention The best way to prevent anticipa- ate emetic risk IV anticancer dexamethasone is the preferred and treatment tory emesis is to achieve good drugs option to prevent acute emesis control of acute and delayed Palonosetron is the preferred emesis 5HT3-RA Benzodiazepines may be helpful, The addition of NK1-RA or olan- as they help reduce the associ- zapine can be considered ated anxiety A combination of a NK1-RA, Radiation-induced emesis Prophylaxis with oral 5-TH3- 5-HT3-RA and dexamethasone prevention RA ± dexamethasone daily is is recommended to prevent car- recommended in patients on boplatin induced acute emesis HEC Prophylaxis against delayed Prophylaxis with oral 5-TH3- emesis is not routinely recom- RA ± short course of dexametha- mended MEC except with those sone daily is recommended therapies frequently associated in patients on moderately with delayed CINV emetogenic radiotherapy Emesis prevention in low and A single antiemetic agent such Patients receiving low emetic minimal emetogenic risk IV as 5-HT3-RA, dexamethasone radiotherapy should receive anticancer drugs or a D2-RA is recommended to prophylaxis or rescue with oral prevent acute emesis with low 5-HT3-RA, dexamethasone (pre- emetogenic agents ferred in SNC RT), or a D2-RA Prophylaxis against delayed Prophylaxis in patients receiving emesis is not routinely recom- minimally emetic radiotherapy is mended with low and minimal not routinely recommended emetogenic agents Concurrent chemoradiotherapy Patients should receive antiemetic If patients experience CINV after treatment according to the low or minimally emetogenic emetogenic potential of the drug, prophylactic antiemetic chemotherapy unless the risk of treatment might be considered emesis induced by the radio- for subsequent cycles using therapy is higher the regimen for the next higher emetic level Emesis prevention in multiday Patients receiving HEC or MEC chemotherapy multiday chemotherapy should receive a 5-HT3-RA plus Author contributions All the authors have contributed equally to the dexamethasone for acute emesis writing of the manuscript. and dexamethasone for delayed emesis Declarations NK1-RA may also be used regimens with significant risk of Conflict of interest MMT reports grants from Bristol Myers Squibb, delayed emesis Roche and AstraZeneca, personal fees from BMS; Astra Zeneca, Roche, If NK1-RA is not included, palon- MSD, Boehringer Ingelheim, Takeda, Sanofi-Aventis, Novartis, Vifor osetron is the preferred serotonin and Bayer outside the submitted work. LCG reports personal fees from antagonist is 5HT3-RA Boehringer Ingelheim,Astra Zeneca, Roche and Bristol Myers Squibb, Emesis prevention in oral anti- Prophylaxis with daily treatment Merck Serono, Ipsen Pharma, Lilly, Amgen, Angelini, Grunenthal, cancer drugs with oral 5HT3-RA is recom- Kyowa Kirin, Mundipharma, Pfizer, Rovi and Leo Pharma. MMG re- mended in patients receiving ports personal fees from Pfizer and Sanofi-Aventis. RDLP, JAV, PC, oral HEC or MEC RLC, MM, RM, MMM, YE have nothing to disclose. Prophylaxis with daily treatment with oral D2-RA is recom- Ethical approval The current study has been performed in accordance mended in patients receiving with the ethical standards laid down in the 1964 Declaration of Hel- oral low- or minimal-emetogenic sinki and its later amendments. oral Breakthrough emesis and rescue After a course refractory to Informed consent Not applicable. antiemetic therapy antiemetic treatment, adjust the scheme for the next cycle to a higher risk group Open Access This article is licensed under a Creative Commons Attri- As rescue therapy, a drug with a bution 4.0 International License, which permits use, sharing, adapta- different mechanism of action tion, distribution and reproduction in any medium or format, as long can be used such as Olanzapine as you give appropriate credit to the original author(s) and the source, or benzodiazepines provide a link to the Creative Commons licence, and indicate if changes were made. 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