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

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Presentation on theme: "Supportive and Palliative Care in the Elderly Sonia Fatigoni Medical Oncology Division, Terni Roma, October 19, 2012 EMESIS."— Presentation transcript:

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

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

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

4 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 Moderate emetic risk (30-90%)

5 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

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

7 Centri superiori Centro del vomito cervelletto Ipotalamo ipofisi orecchio stomaco cuore faringe Nucleo del tratto solitario CTZ M1,D2, 5-HT3 S N C PERIFERIAPERIFERIA movimenti agenti emetogeni VAGOtrigemino Memoria, emozioni

8 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

9 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

10 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 OTHER Alprazolam The control of CINV is possible in about 80-90 % of patient, with the right combination of antiemetic drugs

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

12 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

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

14 To prevent acute vomiting and nausea following chemotherapy of high emetic risk, a three-drug regimen including single doses of a 5-HT 3 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 2009 PERUGIA CONSENSUS CONFERENCE

15 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

16 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. STUDY SCHEME: cisplatin-treated patients Poli-Bigelli S. Cancer 2003 Hesketh PJ. J Clin Oncol 2003

17 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 RESULTS Poli-Bigelli S. Cancer 2003 Hesketh PJ. J Clin Oncol 2003

18 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

19 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 Ondansetron 32 mg - - Dexamethasone 12 mg 8 mg 8 mg bid Ondansetron i.v. Dexamethasone p.o. STUDY SCHEME: cisplatin-treated patients Grunberg SM, JCO 2011

20 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. RESULTS Grunberg SM, JCO 2011

21 FARMACO DAILY DOSE SCHEDULEROUTE CONFIDENCE LEVEL CONSENSUS LEVEL Ondansetron 8 mg 24 mg Single dose IV oral high moderate Granisetron 10 µg/Kg 2 mg Single dose IV oral high Tropisetron 5 mg Single dose IV oral moderate high Dolasetron 0.18 mg/Kg 100 mg Single dose IV oral high Palonosetron 0.25 mg 0.50 mg Single dose IV oral moderate high DOSAGGI E SCHEDULE DEI 5HT 3 ANTAGONISTI nell EMESI ACUTA indotta DA CISPLATINO

22 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 2009 PERUGIA CONSENSUS CONFERENCE

23 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 RISULTATI Poli-Bigelli S. Cancer 2003 Hesketh PJ. J Clin Oncol 2003 * Statisticamente significativo

24 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 dellemesi acuta da cisplatino A partire dalla 24 a ora dopo il cisplatino, sono stati randomizzati a ricevere: - desametasone orale + metoclopramide - desametasone orale + aprepitant

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

26 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

27 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

28 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. STUDY SCHEME: breast cancer pts treated with CTX ± DOX or EPI Warr D, et al. J Clin Oncol, 2005

29 AOD OD No. pts 438 428 p Day 1-5 51 42 0.015 Day 1 76 69 0.034 Day 2-5 55 49 0.064 No nausea days 1-5 33 33 n.s. *Complete response: no vomiting and no rescue therapy RESULTS * Warr D, et al. J Clin Oncol, 2005

30 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 2009 PERUGIA CONSENSUS CONFERENCE

31 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

32 PAL PAL OND PAL PAL DOL 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 RISULTATI Gralla RJ. Ann Oncol 2003 Eisemberg P. Cancer 2003

33 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

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

35 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 RISULTATI

36 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

37 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 2009 PERUGIA CONSENSUS CONFERENCE

38 AOD OD No. pts 438 428 p Day 1 76 69 0.034 Day 2-5 55 49 0.064 Days 1-5 51 42 0.01 No nausea days 1-5 33 33 n.s. Complete response: no vomiting and no rescue therapy RISULTATI Warr D, et al. J Clin Oncol, 2005

39 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 dellemesi acuta indotta da FEC, FAC, AC, EC. A partire dalla 24 a ora dopo la chemioterapia, le pazienti sono state randomizzate a ricevere: - desametasone orale - aprepitant

40 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 dellemesi 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 2009 PERUGIA CONSENSUS CONFERENCE

41 ANTIEMETICS FOR THE PREVENTION OF ACUTE EMESIS INDUCED BY LOW RISK EMETOGENIC CHEMOTHERAPY 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 2009 PERUGIA CONSENSUS CONFERENCE

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

43 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 ANTIEMETICS FOR THE PREVENTION OF ACUTE EMESIS INDUCED BY MINIMAL RISK EMETOGENIC CHEMOTHERAPY 2009 PERUGIA CONSENSUS CONFERENCE

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

45 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 ANTIEMETICS FOR THE PREVENTION OF DELAYED EMESIS INDUCED BY LOW AND MINIMAL RISK EMETOGENIC CHEMOTHERAPY 2009 PERUGIA CONSENSUS CONFERENCE

46 Studio prospettico osservazionale su 1148 pz (22.2% Spagna, 22.1% UK, 18.2 Italia, 13.6% Francia, 9.1% Belgio, 5.6% Svezia, 5.3% Paesi Bassi, 4% Austria)

47

48 ANTIEMETICS IN THE ELDERLY - 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 - Most elderly cancer patients have comorbid conditions that may interfere with their ability to tolerate antiemetic treatments: * diabetes * renal dysfunctions * hepatic dysfunctions

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

50 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

51 ANTIEMETICS IN THE ELDERLY - 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 - It is not necessary to decrease the single dose of the 5-HT3 antagonist in patients with mild or moderate renal and hepatic dysfunction. …about 5-HT3 antagonists

52 ANTIEMETICS IN THE ELDERLY - Finally, the drug –drug interactions are not so important for the 5-HT3 antagonists - Instead, concerning aprepitant...........

53 CAN INCREASE PLASMA CONCENTRATIONS OF COADMINISTERED AGENTS THAT ARE METABOLIZED THROUGH CYP-3A4 ANTIEMETICS IN THE ELDERLY 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 …about aprepitant

54 NK 1 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.

55 CAN INCREASE/DECREASE PLASMA CONCENTRATIONS OF COADMINISTERED AGENTS THAT ARE METABOLIZED THROUGH CYP-2C9 ANTIEMETICS IN THE ELDERLY …about aprepitant 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

56 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 ANTIEMETICS IN THE ELDERLY

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


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