Medical Oncology Division, Terni Supportive and Palliative Care in the Elderly Roma, October 19, 2012 EMESIS Sonia Fatigoni Medical Oncology Division, Terni

Are chemotherapy-induced nausea and vomiting (CINV) still a problem?

High emetic risk (>90%) Intravenous agents Cisplatin Mechlorethamine Streptozocin Cyclophosphamide >=1500 mg/m2 Carmustine Dacarbazine High emetic risk (>90%) Oral agents Hexamethylmelamina Procarbazine

Moderate emetic risk (30-90%) Intravenous agents Oxaliplatin Citarabine > 1 g/m2 Carboplatin Ifosfamide Cyclophosphamide<1500 mg/m2 Doxorubicin Daunorubicin Epirubicin Idarubicin Irinotecan Oral agents Cyclophosphamide Etoposide Temozolomide Vinorelbine Imatinib

CINV Over 50% of cancers occur in the 12% of the population aged 65 years or older CINV can have important negative effects: Quality of Life Dehydration Electrolyte disorders Anorexia/malnutrition

FEATURES OF NAUSEA AND VOMITING ASSOCIATED WITH CHEMOTHERAPY ACUTE NAUSEA AND VOMITING PERSISTENT OR DELAYED NAUSEA AND VOMITING ANTICIPATORY NAUSEA AND VOMITING

Nucleo del tratto solitario Centri superiori Memoria, emozioni S N C Centro del vomito Ipotalamo ipofisi cervelletto Nucleo del tratto solitario CTZ M1,D2, 5-HT3 P E R I F E R I A VAGO trigemino stomaco orecchio faringe cuore movimenti agenti emetogeni

TREATMENT- AND PATIENT-RELATED VARIABLES gender age history of ethanol consumption history of emesis anxiety chemotherapy type chemotherapy dose infusion rate route of administration presence or absence of acute nausea and vomiting nausea and vomiting in previous CT

TREATMENT- AND PATIENT-RELATED VARIABLES Although the risk of experiencing of CINV generally decreased with advancing age, it is an expecially important complication in the elderly because these patients are more sensitive to the effects of cytotoxic cancer therapy The most important factor is the prevention of CINV

The control of CINV is possible with the right combination of Antiemetics CORTICOSTEROIDS Dexametasone, Metilprednisolone 5-HT3 RECEPTOR ANTAGONISTS Ondansetron, Granisetron, Tropisetron, Dolasetron, Palonosetron DOPAMINE ANTAGONISTS Metoclopramide, Domperidone, Prochlorperazine, Aloperidol NK-1 RECEPTOR ANTAGONISTS Aprepitant, Fosaprepitant The control of CINV is possible in about 80-90 % of patient, with the right combination of antiemetic drugs OTHER Alprazolam

LINEE GUIDA AIOM 2010 www.aiom.it Coordinatore: Roila F. Estensori: Caserta C, Fatigoni S. Revisori: Fabi A, Chiara S, Locatelli MC & Raffaele M.

Guideline update for MASCC and ESMO in the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting: results of the Perugia multinational Consensus Conference Roila F., et al. Ann Oncol 2010; 21(Suppl.5):228-39

Uomo di 75 anni con recente diagnosi di SCLC metastatico. CASO CLINICO 1 Uomo di 75 anni con recente diagnosi di SCLC metastatico. Inizia una chemioterapia a base di cisplatino. Quale terapia antiemetica?

2009 PERUGIA CONSENSUS CONFERENCE To prevent acute vomiting and nausea following chemotherapy of high emetic risk, a three-drug regimen including single doses of a 5-HT3 antagonist, dexamethasone and aprepitant (or fosaprepitamt) given before chemotherapy is recommended MASCC: level of scientific confidence: high level of consensus: high ESMO, AIOM: level of evidence I grade of recommendation: A

ADDITION OF THE NEUROKININ 1 RECEPTOR ANTAGONIST APREPITANT TO STANDARD ANTIEMETIC THERAPY IMPROVES CONTROL OF CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING Poli-Bigelli S. Cancer 2003; 97: 3090-8 THE ORAL NEUROKININ-1 ANTAGONIST APREPITANT FOR THE PREVENTION OF CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING: A MULTINATIONAL, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL IN PATIENTS RECEIVING HIGH-DOSE CISPLATIN Hesketh PJ. J Clin Oncol 2003; 21: 4112-19

STUDY SCHEME: cisplatin-treated patients day 1 days 2-3 day 4 Aprepitant 125 mg 80 mg - Ondansetron 32 mg - - Desametasone 12 mg 8 mg 8 mg Ondansetron 32 mg - - Dexamethasone 20 mg 8 mg bid 8 mg bid Aprepitant p.o. Ondansetron i.v. Dexamethasone p.o. Poli-Bigelli S. Cancer 2003 Hesketh PJ. J Clin Oncol 2003

RESULTS Protocol 052 Protocol 054 AOD OD AOD OD No. pts 264 266 283 286 Complete response (%) Day 1 89 78 83 68 Day 2-5 75 56 68 47 no nausea (%) 48 44 49 39 Poli-Bigelli S. Cancer 2003 Hesketh PJ. J Clin Oncol 2003

SINGLE-DOSE FOSAPREPITANT FOR THE PREVENTION OF CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING ASSOCIATED WITH CISPLATIN THERAPY: RANDOMIZED, DOUBLE-BLIND STUDY PROTOCOL-EASE Grunberg SM. J Clin Oncol 2011; 29: 1495-1501

STUDY SCHEME: cisplatin-treated patients day 1 day 2-3 day 4 Aprepitant os 125 mg 80 mg - Ondansetron 32 mg - - Dexamethasone 12 mg 8 mg 8 mg day 1 day 2 days 3-4 Fosaprepitant iv 150 mg Dexamethasone 12 mg 8 mg 8 mg bid Ondansetron i.v. Dexamethasone p.o. Grunberg SM, JCO 2011

RESULTS FOD AOD p Day 1 89.0 88.0 n.s. Day 2-5 74.3 74.2 n.s. Day 1-5 71.9 72.3 n.s. Grunberg SM, JCO 2011

DOSAGGI E SCHEDULE DEI 5HT3 ANTAGONISTI nell’ EMESI ACUTA indotta DA CISPLATINO FARMACO DAILY DOSE SCHEDULE ROUTE CONFIDENCE LEVEL CONSENSUS LEVEL Ondansetron 8 mg 24 mg Single dose IV oral high moderate Granisetron 10 µg/Kg 2 mg Tropisetron 5 mg Dolasetron 0.18 mg/Kg 100 mg Palonosetron 0.25 mg 0.50 mg

2009 PERUGIA CONSENSUS CONFERENCE In patients receiving cisplatin treated with a combination of aprepitant, a 5-HT3 antagonist and dexamethasone to prevent acute nausea and vomiting, the combination of dexamethasone and aprepitant is suggested to prevent delayed emesis, on the basis of its superiority to dexamethasone alone MASCC: level of scientific confidence: high level of consensus: moderate ESMO, AIOM: level of evidence: II grade of recommendation: A

RISULTATI Protocol 052 Protocol 054 AOD OD AOD OD No. pts 264 266 283 286 Complete response (%) Day 1 89* 78 83* 68 Day 2-5 75* 56 68* 47 Day 1-5 73* 52 63* 43 no nausea (%) 48 44 49* 39 * Statisticamente significativo Poli-Bigelli S. Cancer 2003 Hesketh PJ. J Clin Oncol 2003

EMESI RITARDATA DA CISPLATINO: UNO STUDIO DOPPIO-CIECO I.G.A.R. 300 patienti hanno ricevuto una combinazione di aprepitant, palonosetron e desametasone per la prevenzione dell’emesi acuta da cisplatino A partire dalla 24a ora dopo il cisplatino, sono stati randomizzati a ricevere: - desametasone orale + metoclopramide - desametasone orale + aprepitant

Donna di 70 anni operata di cr mammella. CASO CLINICO 2 Donna di 70 anni operata di cr mammella. Inizia una chemioterapia adiuvante con epirubicina e ciclofosfamide. Quale terapia antiemetica?

2009 PERUGIA CONSENSUS CONFERENCE Women receiving a combination of anthracyclines plus cyclophosphamide represent a situation with a particular risk of vomiting and nausea. To prevent acute vomiting and nausea in these women, a three-drug regimen including single doses of a 5-HT3 antagonist, dexamethasone and aprepitant given before chemotherapy is recommended. MASCC: level of scientific confidence: high level of consensus: high ESMO: level of evidence I grade of recommendation: A

EFFICACY AND TOLERABILITY OF APREPITANT FOR THE PREVENTION OF CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING IN PATIENTS WITH BREAST CANCER AFTER MODERATELY EMETOGENIC CHEMOTHERAPY Warr D, et al. J Clin Oncol 2005; 23: 2822-30

STUDY SCHEME: breast cancer pts treated with CTX ± DOX or EPI day 1 days 2-3 Aprepitant 125 mg 80 mg Ondansetron 8/8 mg - Desametasone 12 mg - Ondansetron 8/8 mg 8/8 mg Dexamethasone 20 mg - Aprepitant p.o. Ondansetron p.o. Dexamethasone p.o. Warr D, et al. J Clin Oncol, 2005

RESULTS * AOD OD No. pts 438 428 p Day 1-5 51 42 0.015 No nausea days 1-5 33 33 n.s. *Complete response: no vomiting and no rescue therapy Warr D, et al. J Clin Oncol, 2005

2009 PERUGIA CONSENSUS CONFERENCE A combination of palonosetron plus dexamethasone is recommended for prophylaxis of acute nausea and vomiting in the first course of moderate risk emetogenic chemotherapy non A-C. MASCC: level of scientific confidence: moderate level of consensus: moderate ESMO: level of evidence II grade of recommendation: B

PALONOSETRON IMPROVES PREVENTION OF CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING FOLLOWING MODERATELY EMETOGENIC CHEMOTHERAPY: RESULTS OF A DOUBLE-BLIND RANDOMIZED PHASE III TRIAL COMPARING SINGLE DOSES OF PALONOSETRON WITH ONDANSETRON Gralla RJ. Ann Oncol 2003; 14:1570-77 IMPROVED PREVENTION OF MODERATE CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING WITH PALONOSETRON, A PHARMACOLOGICALLY NOVEL 5-HT3 RECEPTOR ANTAGONIST: RESULTS OF A PHASE III SINGLE-DOSE TRIAL VERSUS DOLASETRON Eisemberg P. Cancer 2003; 98: 2473-82

PAL PAL OND PAL PAL DOL RISULTATI Dose (mg) 0.25 0.75 32 0.25 0.75 100 N° Pts 192 190 188 201 197 194 Day 1 81.0* 73.5 68.6 63.0 57.1 52.9 Day 2-5 74.1* 64.6 55.1 54.0* 56.6* 38.7 Day 1-5 69.3* 58.7 50.3 46.0* 47.1* 34.0 * Statisticamente significativi Gralla RJ. Ann Oncol 2003 Eisemberg P. Cancer 2003

PALONOSETRON PLUS DEXAMETHASONE VERSUS GRANISETRON PLUS DEXAMETASONE FOR PREVENTION OF NAUSEA AND VOMITING DURING CHEMOTHERAPY: A DOUBLE BLIND, DOUBLE-DUMMY, RANDOMIZED, COMPARATIVE PHASE III TRIAL. Saito M. Lancet Oncol 2009; 10: 115-24

day 1 days 2-3 DISEGNO DELLO STUDIO Granisetron 40 mcg/kg --- Dexamethasone 16 mg iv 8 mg iv or 4 mg orally* Palonosetron 0.75 mg iv --- * In 1143 pts submitted to CDDP or M.E.C., respectively Saito M. Lancet Oncol 2009

RISULTATI PD GD p Day 1 75.3 73.3 n.s. Day 2-5 56.8 44.5 0.0001 Day 1-5 51.5 40.4 0.0001

2009 PERUGIA CONSENSUS CONFERENCE If aprepitant is not available, palonosetron should be used with dexamethasone, in women receiving a combination of anthracyclines plus cyclophosphamide MASCC: level of scientific confidence: moderate level of consensus: moderate ESMO: level of evidence II grade of recommendation: B

2009 PERUGIA CONSENSUS CONFERENCE In patients receiving a combination of anthracyclines plus cyclophosphamide treated with a combination of aprepitant, a 5-HT3 receptor antagonist and dexamethasone to prevent acute nausea and vomiting, aprepitant or dexamethasone is suggested to prevent delayed emesis MASCC: level of scientific confidence: moderate level of consensus: moderate ESMO, AIOM: level of evidence II grade of recommendation: B

RISULTATI AOD OD No. pts 438 428 p Day 1 76 69 0.034 Days 1-5 51 42 0.01 No nausea days 1-5 33 33 n.s. Complete response: no vomiting and no rescue therapy Warr D, et al. J Clin Oncol, 2005

EMESI RITARDATA INDOTTA DA MEC: UNO STUDIO DOPPIO-CIECO I.G.A.R. 580 donne hanno ricevuto una combinazione di aprepitant, palonosetron e desametasone per la prevenzione dell’emesi acuta indotta da FEC, FAC, AC, EC. A partire dalla 24a ora dopo la chemioterapia, le pazienti sono state randomizzate a ricevere: - desametasone orale - aprepitant

2009 PERUGIA CONSENSUS CONFERENCE Nei pazienti che ricevono una chemioterapia che non comprende la combinazione di antracicline e ciclofosfamide e per i quali è raccomandato il palonosetron, il trattamento da preferire per la prevenzione dell’emesi ritardata è costituito da desametasone orale per più giorni. Un 5-HT3 antagonista viene considerato come alternativa, nei casi in cui non possa essere usato lo steroide. MASCC: level of scientific confidence: moderate level of consensus: moderate ESMO, AIOM: level of evidence II grade of recommendation: B

ANTIEMETICS FOR THE PREVENTION OF ACUTE EMESIS INDUCED BY LOW RISK EMETOGENIC CHEMOTHERAPY 2009 PERUGIA CONSENSUS CONFERENCE A single agent (such as a low dose of a corticosteroid) is suggested for patients receiving agents of low emetic risk. Level of scientific confidence: no confidence possible Level of consensus: moderate

Low emetic risk (10-30%) Intravenous agents Oral agents Paclitaxel Docetaxel Mitoxantrone Cytarabine<=100 mg/m2 Topotecan Etoposide Pemetrexed Methotrexate Mitomycin Gemcitabine 5-Fluorouracil Bortezomib Cetuximab Trastuzumab Oral agents Capecitabine Fludarabine

ANTIEMETICS FOR THE PREVENTION OF ACUTE EMESIS INDUCED BY MINIMAL RISK EMETOGENIC CHEMOTHERAPY 2009 PERUGIA CONSENSUS CONFERENCE No antiemetic should be routinely administered before chemotherapy in patients without a history of nausea and vomiting. Level of scientific confidence: no confidence possible Level of consensus: high

Minimal emetic risk (<10%) Intravenous agents Bleomycin Busulfan 2-Chlorodeoxyadenosine Fludarabine Vinblastine Vincristine Vinorelbine Bevacizumab Oral agents Chlorambucil Hydroxyurea L-phenylamine mustard 6-Tioguanina Methotrexate Gefitinib Erlotinib

Level of scientific confidence: no confidence possible ANTIEMETICS FOR THE PREVENTION OF DELAYED EMESIS INDUCED BY LOW AND MINIMAL RISK EMETOGENIC CHEMOTHERAPY 2009 PERUGIA CONSENSUS CONFERENCE No antiemetic should be routinely administered for prophylaxis of delayed emesis in patients without a history of delayed nausea and vomiting. Level of scientific confidence: no confidence possible Level of consensus: high

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ANTIEMETICS IN THE ELDERLY Most elderly cancer patients have comorbid conditions that may interfere with their ability to tolerate antiemetic treatments: * diabetes * renal dysfunctions * hepatic dysfunctions Polipharmacy is common in elderly cancer patients. This can interact with antiemetic drugs and can determine poor compliance with other oral drugs. * non-steroidal anti-inflammatory drugs * analgesics

ANTIEMETICS IN THE ELDERLY …about dexamethasone The use of dexamethasone is not contra-indicated if not in presence of diabetic ketoacidosis and active peptic ulcer

ANTIEMETICS IN THE ELDERLY …about 5-HT3 antagonists CHEMOTHERAPY-INDUCED EMESIS IN ELDERLY CANCER PATIENTS: THE ROLE OF 5-HT3 RECEPTOR ANTAGONISTS IN THE FIRST 24 HOURS Aapro M & Johnson J, Gerontology 2005; 51:287-97 PALONOSETRON IMPROVES PREVENTION OF CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING IN ELDERLY PATIENTS Aapro M et al., J Support Oncol, 2005;3:369-74

ANTIEMETICS IN THE ELDERLY …about 5-HT3 antagonists It is not necessary to decrease the single dose of the 5-HT3 antagonist in patients with mild or moderate renal and hepatic dysfunction. All 5-HT3 antagonists have similar efficacy and tolerability and can be used only as a single i.v. or oral dose in the first 24 hrs

ANTIEMETICS IN THE ELDERLY Finally, the drug –drug interactions are not so important for the 5-HT3 antagonists Instead, concerning aprepitant........... Segnalazioni di interazioni tra Ondansetron (metabolizzato attraverso diversi pathway) e paroxetina, tramadolo, cisplatino e ciclofosfamide.

ANTIEMETICS IN THE ELDERLY …about aprepitant CAN INCREASE PLASMA CONCENTRATIONS OF COADMINISTERED AGENTS THAT ARE METABOLIZED THROUGH CYP-3A4 Reduce oral corticosteroid doses by 50% when coadministered with aprepitant and IV doses by 25% Consider potential effects of increased plasma concentrations of midazolam or other benzodiazepines metabolized via CYP3A4 (e.g., alprazolam, triazolam) when coadministered with aprepitant Do not use aprepitant concurrently with pimozide, terfenadine, astemizole, cisapride Caution is advised when aprepitant is administered with the chemotherapeutic agents that are metabolized by CYP-3A4 : etoposide, vinorelbine, docetaxel, and paclitaxel

NK1 ANTAGONISTS: SIDE EFFECTS In two phase III studies the incidence of adverse events was similar with respect to patients who did not receive CYP-3A4 metabolized chemotherapy, while in one, in cisplatin-treated patients, it was higher.

ANTIEMETICS IN THE ELDERLY …about aprepitant CAN INCREASE/DECREASE PLASMA CONCENTRATIONS OF COADMINISTERED AGENTS THAT ARE METABOLIZED THROUGH CYP-2C9 Closely monitor prothrombin time in patients receiving warfarin to establish and maintain dose after completion of 3-day regimen of aprepitant with each chemotherapy course Consider potential effects of decreased plasma concentrations of tolbutamide 

ANTIEMETICS IN THE ELDERLY CAN DECREASE PLASMA CONCENTRATIONS OF COADMINISTERED AGENTS THAT ARE METABOLIZED THORUGH CYP2C9 - Efficacy of oral contraceptives may be reduced during administration of aprepitant; therefore, alternative or backup methods of contraception should be used

Thanks for your attention ! Take Home Messagges Comorbidities and polipharmacy are common in elderly patient Untreated CINV can product important complications in elderly and can decrease the compliance to cancer treatment An efficacy and safety treatment of CINV is possible Educational interventions should be to help elderly patients, supported by their cares More studies are necessary and …more cautions Thanks for your attention !