21 Schnell Kytril - Lebanese Society of Medical Oncology (LSMO)
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Transcript 21 Schnell Kytril - Lebanese Society of Medical Oncology (LSMO)
Kytril: a once-daily 5HT3 receptor
antagonist for control of
chemotherapy-induced nausea
and vomiting (CINV)
Frederick Schnell
Central Georgia Hematology Oncology Associates
Macon, GA, USA
Nausea and vomiting significantly impact
on patients’ quality of life1
Following chemotherapy†, nausea/vomiting scored by patients
(n=80) using 5-day diary and 6-day Functional Living Index
Doctors and nurses (n=9) estimated frequency of acute and
delayed nausea/vomiting
Physicians/nurses
(estimate)
Patients
(actual)
no nausea
69
53
no vomiting
83
72
no nausea
76
43
no vomiting
91
59
Acute (%)
Delayed (%)
†First-cycle
moderately emetogenic chemotherapy
1. Grunberg. Proc Am Soc Clin Oncol 2002;21:250a (Abstract 996)
Nausea and vomiting are rated as major
side-effects of cancer therapy
19831
19952
1
Vomiting
Nausea
2
Nausea
Alopecia
3
Alopecia
Vomiting
Rank
Following the introduction of 5HT3 receptor
antagonists, the rating of vomiting as a side-effect of
chemotherapy has declined2,3
1. Coates et al. Eur J Cancer Clin Oncol 1983;19:203–8
2. de Boer-Dennert et al. Br J Cancer 1997;76:1055–61
3. Griffin et al. Ann Oncol 1996;7:189–95
Pharmacologic control of vomiting
Pharmacologic prevention of vomiting is directed at
blocking vomiting pathways before the administration
of chemotherapy or radiotherapy treatments
Antiemetics may act via the:1
– vomiting center
– chemoreceptor trigger zone
– peripheral receptors (e.g. vagal afferent nerves)
1. Lindley, Blower. Am J Health-Syst Pharm 2000;57:1685–97
Which antiemetic?
Commonly used agents include:
– dopamine-receptor antagonists
– corticosteroids
– benzodiazepines
– antihistamines
– 5HT3-receptor antagonists
5HT3-receptor antagonists are currently the
‘gold-standard’ antiemetic1–4
1. Gralla et al. J Clin Oncol 1999;17:2971–94
2. ASHP. Am J Health-Syst Pharm 1999;56:729–64
3. MASCC. Ann Oncol 1998;9:811–19
4. Koeller et al. Support Care Cancer 2002;10:514–22
Optimizing antiemetic treatment
Awareness must be increased for:
– current guidelines
– evidence supporting guideline recommendations
– incidence of and risk factors for nausea and
vomiting
Antiemetic treatment must be individualized based on
patients’ cytotoxic treatment and patient-specific
factors
Antiemetic guidelines
Differences exist in antiemetic guidelines
– ASCO (American Society of Clinical Oncology)
– MASCC (Multinational Association of Supportive
Care in Cancer)
– ASHP (American Society of Health-Systems
Pharmacists)
Need easy-to-follow, comprehensive consensus
guidelines
Need guidelines from radiation experts that address
needs of radiation therapy patients
Patients need less complicated, effective
antiemetic therapy
The majority of cancer patients receiving radiotherapy
are elderly out-patients
– require fast-acting, long-duration oral antiemetics
Convenient once-daily oral dosing should:
– patient compliance
– control of nausea and vomiting
– patient quality of life
Who is the ‘average’ cancer patient?
Cancer incidence and mortality greatest in elderly
patients1
– ‘average’ patient >65 years2
– increased incidence of co-morbidities with aging
(>3.6 in patients aged >65 years)3
– increased use of concomitant medications in
patients >65 years
(average medications=4.3 per person)4
1. Yancik, Ries. Hematol Oncol Clin North Am 2000;14:17–23
2. Yancik et al. J Clin Oncol 2001;19:1147–51
3. Yancik. Cancer 1997;80:1273–83
4. Jorgensen et al. Ann Pharmacother 2001;35:1004–9
Chemotherapy- and radiation-induced
emesis in the elderly
Elderly are more likely to suffer from chemotherapy
and radiotherapy-induced toxicity1
– may have declining organ function
– co-morbidities
– concomitant medications2,3
Consequences of nausea and vomiting can be
exacerbated in elderly, mainly in patients with
co-morbidities
– dehydration in patients taking diuretics
– exacerbation of cognitive problems
– falls due to extra-pyramidal effects
1. Extermann et al. Hematol Oncol Clin North Am 2000;14:63–77
2. Jorgensen et al. Ann Pharmacother 2001;35:1004–9
3. Hanlon et al. Drugs Aging 2001
Suboptimal antiemetic treatment in the
elderly
Older patients may receive suboptimal antiemetic
treatment because of:
– gastrointestinal changes1 – decreased drug
absorption
– contraindications to corticosteroids (e.g. with
hypertension, diabetes)2
– swallowing problems1,3
– noncompliance to oral therapies4
– possible cognitive impairment/confusion5
Patients need a single drug intake per day
1. Orr, Chen. Am J Physiol Gastrointest Liver Physiol 2002;283:G1226–31
2. http://www.geriatricsyllabus.com/syllabus/main.jsp?cid=SCC-DER-4-2
3. Wilkinson, de Picciotto. S Afr J Commun Disord 1999;46:55–64
4. Lebovits et al. Cancer 1990;65:17–22; 5. Schroder et al. J Neural Transm Suppl 1998;54:51–9
Which 5-HT3-receptor antagonist?
Kytril (granisetron) and ondansetron are currently
indicated for CINV and radiotherapy-induced nausea
and vomiting (RINV)
Differences exist between Kytril and ondansetron
– underlying pharmacology
– duration of efficacy
– hepatic metabolism
– dose adjustments in hepatically impaired patients
– dosing regimens
Drug-drug interactions
Kytril
– not shown to induce or inhibit hepatic metabolism1
– only 5-HT3-receptor antagonist not linked to
CYP2D6 genetic polymorphism1
Ondansetron
– known interactions
• chemotherapeutic agents2
• antidepressants3
• antibiotics4,5
• analgesics6
1. Blower. Cancer J 2002;8:405–14; 2.Cagnoni et al. BMT 1999;24:1–4
3. Stanford, Stanford. J Psychopharmacol 1999;13:313–7
4. www.hivmedicationguide.com/Asp_bin/drug%20interactions.asp
5. www.anaesthetist.com/physiol/basics/metabol/cyp/o.htm
6. DeWitte et al. Anesth Analg 2001;92:1319–21
Hepatic metabolism route
Kytril has not been shown to induce or inhibit hepatic
metabolism1
CYP1A1
CYP1A2
CYP2D6
CYP3A3/4/5
Granisetron
Dolasetron
Tropisetron
*
Ondansetron
*
*Minor
1. Bower. Cancer J 2002;8:405–14
CYP2D6 polymorphism
Genetic polymorphism shown to affect cancer
patients’ response to ondansetron and tropisetron
therapy1
Kytril not at risk for genetic polymorphism
Ultra-rapid metabolizers
(enzyme induction)
Poor metabolizers
(enzyme inhibition)
Metabolism
Metabolism
Efficacy
Risk of AEs
– genetic testing required to determine true risk
AE = adverse event
1. Kaiser et al. J Clin Oncol 2002;20:2805–11
Cardiovascular warnings
Cardiovascular warning
(prescribing information)
Kytril1
Ondansetron2
Dolasetron3
Tropisetron4
1. Kytril (granisetron hydrochloride) Prescribing Information
2. Zofran (ondansetron hydrochloride) Prescribing Information
3. Anzemet (dolasetron mesylate) Prescribing information
4. Navoban (tropisetron) Prescribing Information
Cardiotoxic effects of 5-HT3-receptor
antagonists in healthy adults
Agent
Dose
ECG changes
Clinical effects
Kytril1
10 µg/kg, i.v. (5 min)
No differences
Ondansetron1
10 µg/kg, i.v. (30 s)
32 mg, i.v. (15 min)
mean post-dose QTc
Not clinically
significant
interval*
Dolasetron2
1.2, 1.8, 2.4 mg/kg, i.v. PR, QTc, QRS
intervals**
Dose-related
in heart rate
Ondansetron2
32 mg, i.v.
QTc* & JT** intervals
in heart rate
Kytril3
2 mg, p.o.
Isolated ventricular &
supraventricular ectopic
activity
No sustained
arrhythmias
Dolasetron4
0.6–5.0 mg/kg, i.v.
PR interval & QRS
heart rate at
duration
3 mg/kg or over
*p<0.05; **p<0.001
1. Boike et al. Am J Health-Syst Pharm 1997;54:1172–6
2. Benedict et al. J Cardiovasc Pharmacol 1996;28:53–9
3. Gray et al. Aviat Space Environ Med 1996;67:759–61
4. Hunt et al. J Clin Pharmacol 1995;35:705–12
Dosing regimen: Kytril vs ondansetron
Ondansetron dosed 2–3 times daily
– associated with swallowing problems when
patients are nauseated
Once-daily Kytril dosing
– patient compliance
– patient quality of life
Antiemetic therapy decisions
Therapy should depend on the unique needs of each
patient:
– age/health
– co-morbidities
– concomitant medications
Physicians need to be aware that differences exist
between the available 5HT3-receptor antagonists
A rational choice in the elderly
Co-morbidity assessment
Polypharmacy
Drug–drug interactions
Antiemetic selection that limits complications
Reduced risk of toxicity
Increased possibility of clinical efficacy
Kytril vs ‘conventional’/older antiemetics
Double-blind, placebo-controlled trial
30 patients undergoing single-fraction total body
irradiation (7.5 Gy) received i.v.:
– Kytril, 3 mg‡
– metoclopramide (20 mg), dexamethasone (6 mg/m2),
lorazepam (2 mg), 1 hour prior to radiotherapy
Kytril
Comparator
p value
Complete response* rate
53%
13%
0.02
No vomiting rate
(24 hours)
60%
13%
0.008
*No vomiting, no more than mild nausea and no rescue medication
‡Off-label dose in the USA
1. Prentice et al. Bone Marrow Transplant 1995;15:445–8
Kytril is effective in patients refractory to
‘conventional’ antiemetics
Patients (n=15) refractory to treatment with dopaminereceptor antagonists were scheduled to receive Kytril,
1 mg/day p.o.,‡ 1–2 hours prior to further
radiotherapy*
Results of Kytril therapy
– complete remission of symptoms was observed in
all patients on days 1–3
– immediate remission of nausea and vomiting was
apparent in 33% of patients
*Pelvic, lumboaortic ± iliac/splenic regions or mediastinum radiotherapy
‡Off-label dose
1. Krengli et al. Minerva Med 1996;87:605–8
Kytril vs tropisetron in
pediatric cancer patients
100
Patients (%)
80
p<0.05
88
Kytril
p<0.002
tropisetron
82
74
60
56
40
20
0
Vomiting
Nausea
Aksoylar et al. Pediatr Hematol Oncol 2001;18:397–406
Kytril is well tolerated – adverse events
classed as mild and transient
Most frequently reported adverse events in clinical
trials with Kytril
Occurrence
Kytril1
comparator2
placebo3
Headache
20%
13%
12%
Asthenia
18%
10%
4%
Constipation
14%
16%
8%
Diarrhea
9%
10%
4%
Dyspepsia
6%
5%
4%
Abdominal pain
4%
6%
3%
Event
12
mg p.o. q.d. (n=1450); 2Metochlopramide/dexamethasone; phenothiazines/
dexamethasone; dexamethasone alone; prochlorperazine (n=599); 3(n=185)
Kytril Prescribing Information, chemotherapy data
RINV – a significant clinical problem
Over 80% of patients undergoing radiation of the
upper torso will experience nausea and vomiting1
Fractionated radiotherapy may involve up to
40 fractions over 6–8 weeks, resulting in prolonged
symptoms of emesis2
Uncontrolled nausea and vomiting may lead patients
to delay or refuse future radiotherapy3
1. Danioux et al. Clin Radiol 1979;30:581–4
2. Feyer et al. Support Care Cancer 1998;6:253–60
3. Laszlo. In: Antiemetics and Cancer Chemotherapy, 1983:1–5
Incidence of nausea and vomiting
Overall, 38.7% of patients experienced RINV
Previous chemotherapy increased risk of symptoms
50
p=0.003
45.6%
Patients (%)
40
30
20
10
Previous
chemotherapy
No chemotherapy
33.1%
p=0.028
22.1%
15.1%
0
Vomiting
Nausea
IGARR. Int J Radiat Oncol Biol Phys 1999;44:619–25
Duration of nausea and vomiting
following radiotherapy
Patients experiencing nausea
and vomiting (%)
The symptoms of RINV can last several hours after
therapy1
60
Upper hemibody (n=88)
50
Lower hemibody (n=101)
40
30
20
10
0
0
60
90
120
150
180
210
240
270
300
330
360
Duration of symptoms (min)
1. Danioux et al. Clin Radiol 1979;30:581–4
Kytril has a 24-hour duration of action
Kytril has ‘insurmountable’ 5HT3 receptor binding
Kytril 9 hours
Ondansetron 4 hours
Episodes/hour
Cisplatin
Cyclophosphamide
Carboplatin
First-day early-onset emesis
2
First-day late-onset emesis
1
0
0
4
8
12
16
20
Time after chemotherapy administration (hours)
24
Addition of NK1 receptor antagonists improves
efficacy of standard antiemetic regimen
Standard
5HT3/dex
combination
Triple
combination
p value
Day 1 complete
response rate (%)
68.4
82.8
<0.001
Overall 5-day
response rate (%)
43.3
62.7
<0.001
52.3
72.7
<0.001
Poli-Bigelli et al. (n=523)1
Hesketh et al. (n=521)2
Overall 5-day
response rate (%)
1. Poli-Bigelli et al. Cancer 2003;97:3090–8
2. Hesketh et al. J Clin Oncol 2003;21:4112–9
Kytril effective in combination with
steroids and NK1 receptor antagonists
Combination of 5HT3 receptor antagonist and
dexamethasone improves emetic control but delayed
emesis still problematic
Addition of neurokinin 1 (NK1) receptor antagonists to
5HT3/dexamethasone extends emetic control
– triple combination is now standard of care
International anti-emetic guidelines
Emetic potential of
therapy
High
Moderate
Low
†
†
Acute emesis
Delayed emesis
5HT3 + Dex + NK1
Dex + NK1
5HT3 + Dex
Dex
Dex + metoclopramide
–
Adapted from Multinational Association for Symptom Control in Cancer
Conclusions
The 5-HT3-receptor antagonists are effective for the
treatment of RINV
Kytril (granisetron)
– effective in refractory patients
– more effective than ‘conventional’ antiemetics
– at least as effective as ondansetron
– well tolerated
– once-daily dosing
– low risk for drug-drug interactions
– no cardiovascular warning