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

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

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

4. 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

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. 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

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. 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 % of patient,
with the right combination of
antiemetic drugs
OTHER Alprazolam

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. 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?

14. 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

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:
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:

16. STUDY SCHEME: cisplatin-treated patients
day days day 4
Aprepitant mg mg
Ondansetron mg
Desametasone mg mg mg
Ondansetron mg
Dexamethasone mg mg bid mg bid
Aprepitant p.o Ondansetron i.v. Dexamethasone p.o.
Poli-Bigelli S. Cancer 2003
Hesketh PJ. J Clin Oncol 2003

17. RESULTS Protocol 052 Protocol 054 AOD OD AOD OD
No. pts
Complete response (%)
Day
Day
no nausea (%)
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:

19. STUDY SCHEME: cisplatin-treated patients
day day day 4
Aprepitant os mg mg
Ondansetron mg
Dexamethasone mg mg mg
day day days 3-4
Fosaprepitant iv mg
Dexamethasone mg mg mg bid
Ondansetron i.v. Dexamethasone p.o.
Grunberg SM, JCO 2011

20. RESULTS
FOD AOD p
Day n.s.
Day n.s.
Day n.s.
Grunberg SM, JCO 2011

21. 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

22. 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

23. RISULTATI Protocol 052 Protocol 054 AOD OD AOD OD
No. pts
Complete response (%)
Day * *
Day * *
Day * *
no nausea (%) *
* Statisticamente significativo
Poli-Bigelli S. Cancer 2003
Hesketh PJ. J Clin Oncol 2003

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

25. 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?

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:

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

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

30. 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

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:
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:

32. PAL PAL OND PAL PAL DOL RISULTATI Dose (mg) 0.25 0.75 32 0.25 0.75 100
N° Pts
Day *
Day * * *
Day * * *
* Statisticamente significativi
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:

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

35. RISULTATI
PD GD p
Day n.s.
Day
Day

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. 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

38. RISULTATI AOD OD No. pts 438 428 p Day 1 76 69 0.034
Days
No nausea days n.s.
Complete response: no vomiting and no rescue therapy
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 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

40. 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

41. 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

42. 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

43. 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

44. 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

45. 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

46. Studio prospettico osservazionale su 1148 pz (22. 2% Spagna, 22
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)

48. 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

49. 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

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
…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

52. 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.

53. 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

54. 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.

55. 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 

56. 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

57. 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 !