2009 perugia consensus conference

Supportive and Palliative Care
in the Elderly
Roma, October 19, 2012
EMESIS
Sonia Fatigoni
Medical Oncology Division, Terni
CINV
Are chemotherapy-induced
nausea and vomiting (CINV)
still a problem?
Intravenous agents
• Cisplatin
• Mechlorethamine
• Streptozocin
• Cyclophosphamide >=1500 mg/m2
• Carmustine
• Dacarbazine
High emetic risk
(>90%)
Oral agents
• Hexamethylmelamina
• Procarbazine
Intravenous agents
• Oxaliplatin
• Citarabine > 1 g/m2
• Carboplatin
• Ifosfamide
• Cyclophosphamide<1500 mg/m2
• Doxorubicin
• Daunorubicin
• Epirubicin
• Idarubicin
• Irinotecan
Moderate
emetic risk
(30-90%)
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
Centri
Memoria,
emozioni
superiori
S NC
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
Antiemetics
• CORTICOSTEROIDS
Dexametasone, Metilprednisolone
• 5-HT3 RECEPTOR ANTAGONISTS
Ondansetron, Granisetron, Tropisetron, Dolasetron, Palonosetron
• DOPAMINE ANTAGONISTS
Metoclopramide, Domperidone, Prochlorperazine, Aloperidol
• NK-1 RECEPTOR ANTAGONISTS
The control of CINV is possible
Aprepitant, Fosaprepitant
• OTHER
Alprazolam
in about 80-90 % of patient,
with the right combination of
antiemetic drugs
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
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
Aprepitant
Ondansetron
Desametasone
Ondansetron
Dexamethasone
Aprepitant p.o.
day 1
days 2-3
day 4
125 mg
32 mg
12 mg
80 mg
8 mg
8 mg
8 mg bid
8 mg bid
32 mg
20 mg
Ondansetron i.v.
Dexamethasone p.o.
Poli-Bigelli S. Cancer 2003
Hesketh PJ. J Clin Oncol 2003
RESULTS
Protocol 052
AOD
OD
Protocol 054
AOD OD
264
266
283
286
Day 1
89
78
83
68
Day 2-5
75
56
68
47
no nausea (%)
48
44
49
39
No. pts
Complete response (%)
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
Aprepitant os
Ondansetron
Dexamethasone
day 1
125 mg
32 mg
12 mg
day 2-3
80 mg
8 mg
day 4
8 mg
day 2
days 3-4
Fosaprepitant iv
Ondansetron
Dexamethasone
day 1
150 mg
32 mg
12 mg
-
8 mg bid
Ondansetron i.v.
8 mg
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
Single dose
IV
oral
high
high
high
moderate
Granisetron
10 µg/Kg
2 mg
Single dose
Single dose
IV
oral
high
high
high
high
Tropisetron
5 mg
5 mg
Single dose
Single dose
IV
oral
moderate
moderate
high
high
0.18 mg/Kg
100 mg
Single dose
Single dose
IV
oral
high
high
high
high
0.25 mg
0.50 mg
Single dose
Single dose
IV
oral
moderate
moderate
high
high
Dolasetron
Palonosetron
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
AOD
OD
No. pts
Protocol 054
AOD OD
264
266
283
286
Day 1
89*
78
83*
68
Day 2-5
Day 1-5
75*
73*
56
52
68*
63*
47
43
no nausea (%)
48
44
49*
39
Complete response (%)
* 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
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 CHEMOTHERAPYINDUCED 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
Ondansetron
Desametasone
125 mg
8/8 mg
12 mg
80 mg
-
Ondansetron
Dexamethasone
8/8 mg
20 mg
8/8 mg
-
Aprepitant p.o.
Ondansetron p.o.
Dexamethasone p.o.
Warr D, et al. J Clin Oncol, 2005
RESULTS *
AOD
No. pts
438
OD
428
Day 1-5
51
42
p
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
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
RISULTATI
PAL PAL OND
Dose (mg)
N° Pts
0.25
192
0.75
190
32
188
PAL PAL DOL
0.25 0.75 100
201 197 194
Day 1
81.0* 73.5 68.6
63.0 57.1 52.9
Day 2-5
Day 1-5
74.1* 64.6 55.1
69.3* 58.7 50.3
54.0* 56.6* 38.7
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
DISEGNO DELLO STUDIO
day 1
Granisetron
Dexamethasone
40 mcg/kg
16 mg iv
Palonosetron
0.75 mg iv
Dexamethasone
16 mg iv
days 2-3
--8 mg iv or 4 mg orally*
--8 mg iv or 4 mg orally*
* 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
No. pts
AOD
OD
438
428
Day 1
76
69
p
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
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
Intravenous agents
• Paclitaxel
• Docetaxel
• Mitoxantrone
• Cytarabine<=100 mg/m2
• Topotecan
• Etoposide
• Pemetrexed
• Methotrexate
• Mitomycin
• Gemcitabine
• 5-Fluorouracil
• Bortezomib
• Cetuximab
• Trastuzumab
Low
emetic risk
(10-30%)
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
Intravenous agents
• Bleomycin
• Busulfan
• 2-Chlorodeoxyadenosine
• Fludarabine
• Vinblastine
• Vincristine
• Vinorelbine
• Bevacizumab
Minimal
emetic risk
(<10%)
Oral agents
• Chlorambucil
• Hydroxyurea
• L-phenylamine mustard
• 6-Tioguanina
• Methotrexate
• Gefitinib
• Erlotinib
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
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
- 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
- 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...........
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
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
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