Download Regimen : EOX (Epirubicin, Oxaliplatin and Capecitabine (Xeloda®))

Regimen : EOX (Epirubicin, Oxaliplatin and Capecitabine (Xeloda®))
Indication
Regimen details
Administration
First line palliative treatment for locally advanced, inoperable
oesophago-gastric cancer for patients unsuitable for radical therapy.
Day
Drug
Dose
Route
2
1
Epirubicin
50mg/m
IV bolus
2
1
Oxaliplatin
130mg/m
IV infusion
2
PO
1-21 Capecitabine
625mg/m Twice Daily
Order of administration: epirubicin first, oxaliplatin second.
Epirubicin is administered by slow intravenous bolus in to the side arm
of a fast flowing drip of 0.9% sodium chloride.
Oxaliplatin is administered in 250-500ml Glucose 5% over 2 hours. If
patients experience laryngo-pharyngeal dyaesthesia (see below),
subsequent infusions should be should be given over 4-6 hours.
Infusions must be diluted in Glucose 5% as oxaliplatin is not
compatible with Sodium Chloride 0.9%. Lines must not be
piggybacked or flushed with Sodium Chloride 0.9% immediately after
the Oxaliplatin infusion.
Patients should be observed closely for platinum hypersensitivity
reactions, particularly during the first and second infusions.
Hypersensitivity reactions may occur within a few minutes following the
initiation of the infusion of oxaliplatin. Facilities for the treatment of
hypotension and bronchospasm must be available.
If hypersensitivity reactions occur, minor symptoms such as flushing or
localised cutaneous reactions do not require discontinuation of therapy:
the infusion may be temporarily interrupted and when symptoms
improve re-started at a slower infusion rate. Chlorphenamine 10mg IV
may be administered.
Severe reactions, such as hypotension, bronchospasm or generalised
rash/erythema require immediate discontinuation of oxaliplatin and
appropriate therapy.
Cryotherapy (ice cubes) should NOT be used as they may exacerbate
oxaliplatin-induced pharyngo-laryngeal dyaesthesias. Similarly, laryngopharyngeal dyaesthesia may be exacerbated by exposure to
cold air. If this occurs during infusion, stop infusion immediately and
observe patient. Check oxygen saturation: if normal, an anxiolytic agent
(e.g.lorazepam 1mg SC/PO/IV) may be given. The infusion can then be
restarted at a slower rate (between 4-6 hours)
Capecitabine tablets should be swallowed whole with water within 30
minutes of eating a meal. Available as 500mg and 150mg tablets.
Doses should be banded in accordance with the table below:
Controlled document
Document Number
ASWCS11 GI001
Version Number
1.1.a
Last printed 22/07/2011 13:27:00 * Only valid on day of printing
Page 1 of 6
1.25 – 1.36
Dose level 625mg/m2 bd
Dose (mg) to be given twice daily
800
1.37 – 1.52
1000 morning, 800 evening
1.53 – 1.66
1000
1.67– 1.78
1150 morning, 1000 evening
1.79– 1.90
1150
1.91 – 2.04
1500 morning, 1000 evening
2.05 – 2.16
1300
2.17 – 2.32
1500 morning, 1300 evening
≥2.33
1500
Body Surface Area (m2)
Frequency
Extravasation
Premedication
Emetogenicity
Additional
recommended
supportive
medication
Pre-treatment
evaluation
Regular
investigations
Standard limits for
administration to go
ahead – if blood results
not within range,
authorisation to administer
must be given by
prescriber/consultant
Controlled document
Every 21 days
Maximum 8 cycles
Epirubicin is a vesicant (Group 5)
Oxaliplatin is an exfoliant (Group 4)
Capecitabine is an oral agent.
None usually required.
1. Patients who have previously experienced Grade 1 or 2 platinum
hypersensitivity should be pre-medicated with as follows:
• 45 minutes prior to Oxaliplatin: Dexamethasone 20mg IV bolus
• 30 minutes prior to Oxaliplatin: Chlorphenamine 10mg IV bolus
and Ranitidine 50 mg IV bolus diluted in at least 20ml Sodium
Chloride 0.9% and given over at least 2 minutes.
2. Patients who develop peripheral neuropathy may be considered for
calcium gluconate 1g and magnesium sulphate 1g given together in
250mL 5% Glucose IV over 20 minutes pre- and post-oxaliplatin
infusion. Caution is required in giving this treatment to patients with
known hypercalcemia or those receiving therapy with digoxin or
thiazide diuretics.
This regimen has high emetogenic potential – refer to local protocol
•
•
•
Mouthwashes as per local policy.
Loperamide 4mg po stat then 2mg prn if diarrhoea develops.
Pyridoxine 50 mg tds reduces the severity of plantar-palmar
erythrodyesthesia (PPE). It should be given for any grade PPE
and should be continued until the end of treatment.
FBC
Baseline – results valid for 14 days
U+E
Baseline – results valid for 14 days
LFT
Baseline – results valid for 14 days
FBC
Results valid for 72 hrs
U+E
Results valid for 7 days
LFT
Results valid for 7 days
Ca2+ and Mg2+
Results valid for 7 days
CT scan
Perform after 4 cycles of treatment
Neutrophil count
≥1.0 x109/L
Platelet count
≥75 x109/L
Creatinine clearance
≥50 ml/min
Bilirubin
<1.5 x ULN
Document Number
ASWCS11 GI001
Version Number
1.1.a
Last printed 22/07/2011 13:27:00 * Only valid on day of printing
Page 2 of 6
Dose
modifications
Haematological
toxicity
Renal impairment
Neutrophil
count
≥ 1.0
0.5-0.9
Platelet
count
≥ 75
50-74
CrCl (mL/min)
>50
30-49
<30
Action
Go ahead
Stop
capecitabine and
delay next cycle
until count
Dose modification
once count recovery
Full dose
Restart capecitabine at
full dose, epirubicin at
75% dose and
oxaliplatin at 100mg/m2
Capecitabine
Oxaliplatin
100%
100%
75%
75%
Contra-indicated
Omit
Epirubicin
100%
100%
Omit
Hepatic
impairment
Bilirubin
Epirubicin
<1.5 x ULN
100%
1.5-3 x ULN
50%
3-5 x ULN
25%
>5 x ULN
Omit
Capecitabine: Lack of information available. In patients with mild to moderate
hepatic dysfunction due to liver metastases (<3 x ULN bilirubin; <5 x ULN
AST/ALT). Probably no dose reduction necessary: clinical decision
Oxaliplatin: Little information available. Probably no dose reduction
necessary: clinical decision
NCI Common
toxicity criteria
Toxicity
Neurotoxicity
(Oxaliplatin)
Controlled document
Document Number
ASWCS11 GI001
Definition
Grade 1
paraesthesia
Grade 2
paraesthesia
persisting until
next cycle
Version Number
1.1.a
Last printed 22/07/2011 13:27:00 * Only valid on day of printing
Dose adjustment
100%
Reduce dose to 100mg/m2
Page 3 of 6
Grade 3
Reduce dose to 100mg/m2
paraesthesia >7
days but resolved
before next cycle
Grade 3
Discontinue oxaliplatin
paraesthesia
persisting until
next cycle or
Grade 4 of any
duration
Acute Cold-related Dysaesthesia (CRD): Many patients experience
transient paraesthesia of hands & feet. Onset is during or within hours of
infusion, and resolves within minutes to a few days. Symptoms are
exacerbated by cold, so patient should be advised to avoid cold. Does not
require treatment or dose reduction.
Acute laryngopharyngeal dysaesthesia: Some patients experience
laryngopharyngeal dysaesthesia (unpleasant sensations in the throat).
Onset is during or within hours of infusion, and resolves within minutes to
a few days. Symptoms are exacerbated by cold, so patient should be
advised to avoid cold drinks. Does not require treatment or dose reduction.
Palmar-Plantar
Erythrodyesthesia
(Capecitabine)
Diarrhoea/Mucositis
and Stomatitis *
(Capecitabine)
Grade 1:Minimal
skin changes or
dermatitis (e.g.,
erythema, edema,
or hyperkeratosis)
without pain
Grade 2: Skin
changes (e.g.,
peeling, blisters,
bleeding, edema,
or hyperkeratosis)
with pain; limiting
instrumental ADL
Grade 3: Severe
skin changes (e.g.,
peeling, blisters,
bleeding, edema,
or hyperkeratosis)
with pain; limiting
self care ADL
Grade 1
Grade 2
Grade 3
Controlled document
Document Number
ASWCS11 GI001
Version Number
1.1.a
Last printed 22/07/2011 13:27:00 * Only valid on day of printing
100%
1st appearance: delay until
resolved to ≤ Grade 1 and then
resume at 100%
2nd appearance: delay until
resolved to ≤ Grade 1 and then
resume at 75%
3rd appearance: delay until
resolved to ≤ Grade 1 and then
resume at 50%
1st appearance: delay until
resolved to ≤ Grade 1 and then
resume at 75%
2nd appearance: delay until
resolved to ≤ Grade 1 and then
resume at 50%
3rd appearance: discontinue
100%
1st appearance: delay until
resolved to ≤ Grade 1 and then
resume at 100%
2nd appearance: delay until
resolved to ≤ Grade 1 and then
resume at 75%
3rd appearance: delay until
resolved to ≤ Grade 1 and then
resume at 50%
1st appearance: delay until
resolved to ≤ Grade 1 and then
Page 4 of 6
Adverse effects –
the contents of the table
indicate the adverse
effects that should be
documented on consent
to treatment forms
Significant drug
interactions – For
full details consult
product
literature/reference texts
Comments
Cumulative Doses
References
Controlled document
resume at 75%
2nd appearance: delay until
resolved to ≤ Grade 1 and then
resume at 50%
3rd appearance: discontinue
Grade 4
Discontinue
* Note that severe diarrhoea and/or severe mucositis early in the first
treatment cycle can be the first presenting toxicity due to DPD enzyme
deficiency. This can lead to potentially fatal neutropenia.
Serious side effects
Frequently occurring side
effects
Myelosuppression (common)
Cardiomyopathy / toxicity
Secondary malignancy
Peripheral Neuropathy
Diarrhoea
Palmar-plantar
erythrodyesthesia
Ovarian failure/infertility
Alopecia (complete)
Nephrotoxicity
Stomatitis/ Mucositis
Nausea and vomiting
Pink urine for 24 hours post
epirubicin
Fatigue
Other
dysgeusia, headache, dizziness
Warfarin/courmarin anticoagulants Avoid use – switch patients to low
molecular weight heparin during treatment – elevations in INR
Oxaliplatin:
Aminoglycosides: increased risk of nephrotoxicity and possibly of ototoxicityavoid concomitant use
Diuretics: increased risk of nephrotoxicity and ototoxicity when platinum
compounds given with diuretics
Capecitabine:
Phenytoin and fosphenytoin – toxicity has occurred during concomitant
capecitabine therapy – monitor levels regularly.
Sorivudine and its analogues – co-administration causes increased
fluoropyrimidine toxicity which may be fatal
Allopurinol – A decrease in capecitabine activity as been shown when taken
in combination of allopurinol. Avoid if possible.
Folinates Avoid concomitant use of folinic and folic acid – enhanced toxicity
of capecitabine
Antacids – the use of antacids with capecitabine can decrease absorption –
avoid.
Dihydropyrimidine dehydrogenase (DPD) deficiency can result in severe
toxicity secondary to reduced fluorouracil metabolism – avoid use of
capecitabine in patients with known DPD deficiency
Cardiotoxicity has been associated with fluoropyrimidine therapy, with adverse
events being more common in patients with a prior history of coronary artery
disease. Caution must be taken in patients with a history of significant cardiac
disease, arrhythmias or angina pectoris.
Epirubicin has a life time maximum cumulative dose of 900mg/m2
•
Cunningham D, Rao S, Starling N, Iveson T, Nicolson M, Coxon F, et
al. Randomised multicentre phase III study comparing capecitabine
Document Number
ASWCS11 GI001
Version Number
1.1.a
Last printed 22/07/2011 13:27:00 * Only valid on day of printing
Page 5 of 6
•
•
•
•
•
•
•
with fluorouracil and oxaliplatin with cisplatin in patients with advanced
oesophago-gastric (OG) cancer: The REAL 2 trial. J Clin Oncol 2006.
24;18S (June 20 supplement abstract):4017.
Cunningham D, Starling N, Rao S, Iveson T, Nicolson M, Coxon F,
Middleton G, et al. Capecitabine and Oxaliplatin for Advanced
Esophagogastric Cancer N Engl J Med 2008; 358: 36-46.
Daniels S. North London Cancer Network, Dose adjustment for
cytotoxics in hepatic impairment [internet]. accessed 12/01/2011
available at http://www.bopawebsite.org/tikidownload_file.php?fileId=621
Daniels S. North London Cancer Network, Dose adjustment
forcytotoxics in renal impairment [internet]. accessed 12/01/2011
available at http://www.bopawebsite.org/tikidownload_file.php?fileId=620
Baxter K, editor. Stockley’s Drug Interactions. Pharmaceutical Press;
2009. Accessed online on 06/05/09 available at
https://www.medicinescomplete.com/mc/
Allwood M, Stanley A, Wright P, editors. The cytotoxics handbook. 4th
ed. Radcliffe Medical Press . 2002.
Summary of Product Characteristics Epirubicin Hydrochloride 2mg/ml
Injection (Hospira) [internet]. accessed 23/02/2011 available from
http://www.medicines.org.uk/EMC/medicine/18609/SPC Summary of
Product Characteristics Oxaliplatin Hospira 5mg/ml concentration for
solution for infusion (Hospira) [internet]. accessed 14/01/2011
available from http://www.medicines.org.uk/EMC/medicine/20911/SPC
Summary of Product Characteristics Xeloda® (Capecitabine)
500mg and 150mg Tablets (Roche) [internet], accessed
23/02/2011 available from
http://www.medicines.org.uk/EMC/medicine/4619/SPC/Xeloda/
Document title
Document number
Approval date
Written by
EOX (Epirubicin, Oxaliplatin and Capecitabine (Xeloda®))
ASWCS11 GI001
Checked by
James Carr, Network Pharmacist,
ASWCS
Authorised by
Jeremy Braybrooke, Chair ASWCS
Drugs and Therapeutics Committee
Review date
Document reviewed by
Version number
Summary of changes
19/07/2013
Controlled document
19/07/2011
Stephen Falk, Consultant Clinical
Oncologist BHOC
1.1.a
Version
Steve Falk
James Carr
Jeremy
Braybrooke
1.1.a
Document Number
ASWCS11 GI001
Version Number
1.1.a
Last printed 22/07/2011 13:27:00 * Only valid on day of printing
Page 6 of 6
Digitally signed by Steve Falk
DN: cn=Steve Falk, o, ou, email=james.
[email protected], c=GB
Date: 2011.07.22 13:30:49 +01'00'
Digitally signed by James Carr
DN: cn=James Carr, o=ASWCS, ou=Network
Pharmacist, [email protected],
c=GB
Date: 2011.07.22 13:31:18 +01'00'
Digitally signed by Jeremy Braybrooke
DN: cn=Jeremy Braybrooke, o, ou,
[email protected], c=GB
Date: 2011.07.22 13:31:52 +01'00'