supportive and palliative care in the elderly sonia fatigoni medical oncology division, terni roma,...

Supportive and Palliative Care in the Elderly

Sonia FatigoniMedical Oncology Division, Terni

Roma, October 19, 2012

EMESIS

CINV

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

Intravenous agents

• Cisplatin• Mechlorethamine• Streptozocin • Cyclophosphamide >=1500 mg/m2• Carmustine • Dacarbazine

Oral agents

• Hexamethylmelamina• Procarbazine

High emetic risk (>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

Moderate emetic risk (30-90%)

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 FEATURES OF NAUSEA AND VOMITINGVOMITING

ASSOCIATED WITH CHEMOTHERAPYASSOCIATED WITH CHEMOTHERAPY

• ACUTE NAUSEA AND VOMITING

• PERSISTENT OR DELAYED NAUSEA AND VOMITING

• ANTICIPATORY NAUSEA AND VOMITING

Centri superiori

Centro del vomito

cervelletto

Ipotalamo ipofisi

orecchio

stomaco

cuore

faringe

Nucleo del tratto solitario

CTZ M1,D2, 5-

HT3

S N C

P E

R I F E

R I A

movimentiagenti emetogeni

VAGO trigemino

Memoria, emozioni

TREATMENT- AND PATIENT-RELATED TREATMENT- AND PATIENT-RELATED VARIABLESVARIABLES

• 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 TREATMENT- AND PATIENT-RELATED VARIABLESVARIABLES

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

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

LINEE GUIDA AIOM 2010www.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

CASO CLINICO 1CASO CLINICO 1

Uomo di 75 anni con recente diagnosi di SCLC metastatico.

Inizia una chemioterapia a base di cisplatino.

Quale terapia antiemetica?

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

2009 PERUGIA CONSENSUS CONFERENCE

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

day 1 days 2-3 day 4

Aprepitant 125 mg 80 mg -

Ondansetron 32 mg - -

Desametasone 12 mg 8 mg 8 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

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

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

day 1 day 2-3 day 4

Aprepitant os 125 mg 80 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.

STUDY SCHEME: cisplatin-treated patients

Grunberg SM, JCO 2011

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

FARMACODAILY DOSE

SCHEDULE ROUTECONFIDENCE

LEVELCONSENSUS

LEVEL

Ondansetron8 mg

24 mg

Single dose

Single dose

IV

oral

high

high

high

moderate

Granisetron10 µg/Kg

2 mg

Single dose

Single dose

IV

oral

high

high

high

high

Tropisetron5 mg

5 mg

Single dose

Single dose

IV

oral

moderate

moderate

high

high

Dolasetron 0.18 mg/Kg

100 mg

Single dose

Single dose

IV

oral

high

high

high

high

Palonosetron0.25 mg

0.50 mg

Single dose

Single dose

IV

oral

moderate

moderate

high

high

DOSAGGI E SCHEDULE DEI 5HTDOSAGGI E SCHEDULE DEI 5HT33 ANTAGONISTI ANTAGONISTI nell’ EMESI ACUTA indotta DA CISPLATINOnell’ EMESI ACUTA indotta DA CISPLATINO

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: moderateESMO, AIOM: level of evidence: II grade of recommendation: A


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

EMESI RITARDATA DA CISPLATINO: EMESI RITARDATA DA CISPLATINO: UNO STUDIO DOPPIO-CIECO UNO STUDIO DOPPIO-CIECO

I.G.A.R.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

CASO CLINICO 2CASO CLINICO 2

Donna di 70 anni operata di cr mammella.

Inizia una chemioterapia adiuvante con epirubicina e ciclofosfamide.

Quale terapia antiemetica?


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: highESMO: 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

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 ptstreated with CTX ± DOX or EPI

Warr D, et al. J Clin Oncol, 2005

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 *


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: moderateESMO: 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

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

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

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

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


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: moderateESMO: level of evidence II grade of recommendation: B

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: moderateESMO, AIOM: level of evidence II grade of recommendation: B


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


EMESI RITARDATA INDOTTA DA MEC: EMESI RITARDATA INDOTTA DA MEC: UNO STUDIO DOPPIO-CIECO I.G.A.R.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

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: moderateESMO, AIOM: level of evidence II grade of recommendation: B


ANTIEMETICS FOR THE PREVENTION OF ACUTE ANTIEMETICS FOR THE PREVENTION OF ACUTE EMESIS INDUCED BY LOW RISK EMETOGENIC EMESIS INDUCED BY LOW RISK EMETOGENIC

CHEMOTHERAPYCHEMOTHERAPY

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


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%)

No antiemetic should be routinely administered before chemotherapy in patients without a history of nausea and vomiting.


•Level of consensus: high

ANTIEMETICS FOR THE PREVENTION OF ACUTE ANTIEMETICS FOR THE PREVENTION OF ACUTE EMESIS INDUCED BY MINIMAL RISK EMETOGENIC EMESIS INDUCED BY MINIMAL RISK EMETOGENIC

CHEMOTHERAPYCHEMOTHERAPY


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%)

No antiemetic should be routinely administered for prophylaxis of delayed emesis in patients without a history of delayed nausea and vomiting.


•Level of consensus: high

ANTIEMETICS FOR THE PREVENTION OF DELAYED ANTIEMETICS FOR THE PREVENTION OF DELAYED EMESIS INDUCED BY LOW AND MINIMAL RISK EMESIS INDUCED BY LOW AND MINIMAL RISK

EMETOGENIC CHEMOTHERAPYEMETOGENIC CHEMOTHERAPY


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)

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


- The use of dexamethasone is not contra-indicated if not in presence of diabetic ketoacidosis and active peptic ulcer

…about dexamethasone


- 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


- Finally, the drug –drug interactions are not so important for the 5-HT3 antagonists

- Instead, concerning 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

…about aprepitant

CAN INCREASE/DECREASE PLASMA CONCENTRATIONS OF COADMINISTERED AGENTS THAT ARE METABOLIZED THROUGH CYP-2C9


…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

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

supportive and palliative care in the elderly sonia fatigoni medical oncology division, terni roma,...

Documents

vomiting slide

vomiting nausea

emesis slide

vomiting cinv

emozioni slide

prevention of cinv slide

chemotherapy acute nausea

chemotherapyinduced