Download Regimen : Oxaliplatin+Modified de Gramont (FOLFOX)

Regimen : Oxaliplatin+Modified de Gramont (FOLFOX)
Indication
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Regimen details
Administration
Adjuvant treatment of stage III (Duke's C) colon cancer after
complete resection of primary tumour
Treatment of first line or second line palliative therapy for stage
IV or relapsed disease
(For performance status 0 and 1 patients only)
Day
Drug
Dose
Route
2
1
IV infusion
Oxaliplatin
85mg/m
IV infusion
1
Calcium Folinate (Folinic acid) 350 mg
2
IV bolus
1
Fluorouracil
400mg/m
2
1-3*
Fluorouracil
IV infusion
2400mg/m
over 46 hours
*i.e. single dose, commenced day 1, finished day 3
Order of administration: oxaliplatin and calcium folinate first (together),
fluorouracil bolus second, fluorouracil infusion third.
Administer calcium folinate and oxaliplatin concomitantly via a 3-way
tap/Y-site connector over 2 hours. If patients experience laryngopharyngeal 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.
The smaller fluorouracil dose is administered by slow intravenous bolus
into the side-arm of a fast flowing drip of 0.9% sodium chloride.
The larger fluorouracil dose is administered by intravenous infusion (via
central venous catheter and ambulatory infusor device or continuous
peripheral IV infusion) over 46 hours. (If given via peripheral infusion, the
dose is split in two and given in 2x1 litre 0.9% Sodium Chloride).
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
Controlled document
Document Number
ASWCS11 GI016
Version Number
1.1.a
Last printed 22/07/2011 18:30:00 * Only valid on day of printing
Page 1 of 6
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)
Frequency
Extravasation
Premedication
Emetogenicity
Additional
recommended
supportive
medication
Pre-treatment
evaluations
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
Calcium levofolinate is NOT equivalent to calcium folinate/folinic
acid/calcium leucovorin. (Calcium levofolinate is a single isomer of folinic
acid and the dose is generally 175mg i.e. half that of calcium folinate).
Every 14 days
Maximum 12 cycles
Oxaliplatin is an exfoliant (Group 4)
Fluorouracil is an inflammatant (Group 2)
Calcium Folinate (Folinic acid) is neutral (Group 1)
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 moderate-high emetogenic potential – refer to local
protocol
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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 7 days
U+E
Baseline – results valid for 7 days
LFT
Baseline – results valid for 7 days
CEA
Baseline – results valid for 7 days
FBC
Results valid for 72 hrs
U+E
Results valid for 7 days
LFT
Results valid for 7 days
2+
Ca
Results valid for 7 days
CEA
Results valid for 7 days
(perform
monthly)
CT scan Perform after 6 cycles of treatment
Neutrophil count
≥1.0 x 109/L
Platelet count
≥75 x 109/L
Creatinine clearance
≥50ml/min
Bilirubin
≤26micromol/L
Document Number
ASWCS11 GI016
Version Number
1.1.a
Last printed 22/07/2011 18:30:00 * Only valid on day of printing
Page 2 of 6
Dose modifications
Haematological
Defer therapy for 1 week if neutrophils <1.0 x 109/L or platelets < 75 x 109/L
toxicity
Renal
CrCl (ml/min)
Oxaliplatin Dose
Fluorouracil
Folinic Acid
impairment
Dose
Dose
≥50
100%
100%
100%
30-49
50%
100%
100%
10-29
Omit
100%
100%
<10
Omit
Consider dose
100%
reduction
Hepatic
Bilirubin
AST
Oxaliplatin
Fluorouracil
Folinic Acid
impairment
(micromol/L)
(x ULN)
Dose
Dose
Dose
≤26
≤1.5
100%
100%
100%
27-51
≤3
100%
100% *
100%
†
52-85
3-5
50%
100% **
100%
Contra-indicated
>85 or
>5
*Consider reducing fluorouracil dose by 33%
**Consider reducing fluorouracil dose by 50%
(Doses may be increased back to 100% if there is no toxicity)
†
Note: significant hepatic impairment may indicate disease progression: always discuss
deteriorating hepatic function with consultant.
NCI Common
Toxicity
Definition
Dose adjustment
toxicity criteria
Reduce subsequent cycles of
Febrile
ANC <0.5 x
neutropenia
Thrombocytopenia
109/L plus fever
requiring IV
antibiotics +/hospitalisation
Platelets 10-49 x
109/L
Platelets< 10 x
109/L
Stomatitis/Mucositis
Grade 2
Grade 3
Diarrhoea*
Grade 4
Grade 2
Grade 3
Controlled document
Document Number
ASWCS11 GI016
Version Number
1.1.a
Last printed 22/07/2011 18:30:00 * Only valid on day of printing
fluorouracil by 50% and reduce
dose of oxaliplatin to 55mg/m2.
Delay treatment until counts ≥ 75 x
109/L. Reduce subsequent doses of
oxaliplatin to 65mg/m2. On second
occurrence, reduce dose of
oxaliplatin to 55mg/m2.
Delay treatment until counts ≥ 75 x
109/L. Reduce subsequent doses of
oxaliplatin to 55mg/m2. On second
occurrence, discuss with consultant.
Defer until ≤ Grade 1. Reduce all
subsequent doses of fluorouracil by
20%
Defer until ≤ Grade 1. Reduce all
subsequent doses of fluorouracil by
50%. Reduce Oxaliplatin to
65mg/m2.
Discontinue treatment
Defer until ≤ Grade 1. Reduce all
subsequent doses of fluorouracil by
20%
Defer until ≤ Grade 1. Add
Ciprofloxacin 250mg bd and reduce
all subsequent doses of fluorouracil
by 50%. Reduce Oxaliplatin to
Page 3 of 6
Grade 4
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
Controlled document
65mg/m2.
Discontinue treatment
*Patients presenting with diarrhoea must be carefully monitored until the
symptoms have disappeared completely, since a rapid (sometimes fatal)
deterioration can occur.
Palmar-Plantar
Grade 2
Defer until ≤ Grade 1. Reduce all
Erythrodyesthesia
subsequent doses of fluorouracil by
(PPE)
20%
Grade 3/4
Defer until ≤ Grade 1. Reduce all
subsequent doses of fluorouracil by
50%
Peripheral
Grade 2/3
Reduce oxaliplatin to 65mg/m2.
Neuropathy
Grade 4
Discontinue oxaliplatin.
Rare or serious side effects
Frequently occurring side effects
Mucositis/Stomatitis
Palmar-plantar erythema (Hand-Foot
Syndrome)
Diarrhoea
Myelosuppression and neutropenic
sepsis
Cardiac toxicity including tachycardia
Alopecia
and angina pectoris
Ocular toxicity including excessive
Nausea & vomiting
lacrimation, blocked tear ducts, visual
changes and photophobia.
Ototoxicity
Peripheral Neuropathy
Interstitial lung disease; pulmonary
Epistaxis
fibrosis*
Thrombocytopenia
Deep Vein Thrombosis; pulmonary
embolism
Laryngopharyngeal dyesthesia**
* In the case of unexplained non-productive cough, dyspnoea, crackles or
radiological pulmonary infiltrates, oxaliplatin should be discontinued until further
pulmonary investigations exclude interstitial lung disease.
**Needs to be distinguished from platinum hypersensitivity reactions
Other
Transient cerebellar syndrome, confusion, thrombophlebitis,
hypokalaemia
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
Fluorouracil:
Allopurinol: may potentiate cytotoxic effect-avoid concomitant use
Clozapine: increased risk of agranulocytosis, avoid concomitant use
Warfarin/coumarin anticoagulants: increased or fluctuating anticoagulant
effects. Avoid if possible: in the first instance, consider switching patient to a low
molecular weight heparin during treatment or if the patient continues taking an
oral anticoagulant monitor the INR at least once a week and adjust dose
accordingly.
Digoxin tablets: fluorouracil may reduce digoxin absorption (give digoxin in
liquid form)
Metronidazole and Cimetidine: inhibit metabolism of fluorouracil (increased
Document Number
ASWCS11 GI016
Version Number
1.1.a
Last printed 22/07/2011 18:30:00 * Only valid on day of printing
Page 4 of 6
exposure and risk of toxicity)
Phenytoin: reduced absorption of phenytoin.
Calcium Folinate:
Antiepileptic drugs (phenobarbital, primidone, phenytoin): may increase the
frequency of seizures
Anti-folates (co-trimoxazole/trimethoprim, pyrimethamine): efficacy may be
reduced by concomitant use of leucovorin.
Comments
Dihydropyrimidine dehydrogenase (DPD) deficiency can result in severe
toxicity secondary to reduced fluorouracil metabolism – avoid use 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.
Cumulative
Doses
References
Calcium levels should be monitored in patients receiving this regimen and
calcium supplementation should be provided if where hypocalcaemia
occurs.
N/A
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Controlled document
Cheeseman SL, Joel SP, Chester JD, Wilson G, Dent JT, Richards
FJ, Seymour MT. A 'modified de Gramont' regimen of fluorouracil,
alone and with oxaliplatin, for advanced colorectal cancer. Br J
Cancer 2002 87(4): 393-9.
de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy
J, et al. Leucovorin and Fluorouracil with or without Oxaliplatin as
first-line treatment in advanced colorectal cancer. J Clin Oncol 2000
18: 2938-2947
Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Ramanathan RK,
Williamson SK, et al. A Randomized Controlled Trial of Fluorouracil
Plus Leucovorin, Irinotecan, and Oxaliplatin Combinations in Patients
With Previously Untreated Metastatic Colorectal Cancer. J Clin Oncol
2004; 22 (1):23-30
Louvet C, de Gramont A. Colorectal cancer: integrating Oxaliplatin.
Curr Treat Options in Oncol 2003; 4 (5): 405–411.
Maindrault-Goebel F, Louvet C, Andre T, Carola E, Lotz JP, Molitor
JL, et al. Oxaliplatin added to the simplified bimonthly leucovorin and
5-fluorouracil regimen as second-line therapy for metastatic
colorectal cancer (FOLFOX6). GERCOR. Eur J Cancer 1999
35(9):1338-42
Maindrault-Goebel F, de Gramont A, Louvet C, André T, Carola E,
Mabro M, et al. High-dose intensity oxaliplatin added to the simplified
bimonthly leucovorin and 5-fluorouracil regimen as second-line
therapy for metastatic colorectal cancer (FOLFOX 7). Eur J Cancer
2001 37(8): 1000-5. Erratum in Eur J Cancer. 2004 40(16):2533.
Tournigand C, Louvet C, Quinaux E, Andre T, Lledo G, Flesch M,
et al. FOLFIRI followed by FOLFOX versus FOLFOX followed by
FOLFIRI in metastatic colorectal cancer (MCRC): Final results of a
phase III study. Proc Am Soc Clin Oncol 2001 20: abstract 494
Gamelin L, Boisdron-Celle M, Delva R, Guérin-Meyer V, Ifrah N,
Morel A, Gamelin E, et al. Prevention of oxaliplatin-related
neurotoxicity by calcium and magnesium infusions: a retrospective
Document Number
ASWCS11 GI016
Version Number
1.1.a
Last printed 22/07/2011 18:30:00 * Only valid on day of printing
Page 5 of 6
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Document title
Document number
Approval date
Written by
Checked by
Authorised by
Review date
Document reviewed by
Version number
Summary of changes
Controlled document
study of 161 patients receiving oxaliplatin combined with 5Fluorouracil and leucovorin for advanced colorectal cancer. Clin
Cancer Res 2004 10 (12 Pt 1): 4055-4061
National Institute for Health and Clinical Excellence. Technology
Appraisal 93. Irinotecan, oxaliplatin and raltitrexed for the treatment
of advanced colorectal cancer. [internet] accessed 14/01/2011,
available at
http://www.nice.org.uk/nicemedia/live/11562/33132/33132.pdf
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 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 Fluorouracil 50mg/ml injection
(Hospira) [internet]. accessed 12/01/2011 available from
http://emc.medicines.org.uk/document.aspx?documentId=636
Summary of Product Characteristics Calcium Folinate 10mg/mL
injection (Hospira) [internet] accessed 14/01/2011 available from
http://www.medicines.org.uk/EMC/medicine/8286/SPC
Oxaliplatin+Modified de Gramont
ASWCS11 GI016
19/07/2011
Stephen Falk, Consultant Clinical
Oncologist BHOC
James Carr, Network Pharmacist,
ASWCS
Jeremy Braybrooke, Chair ASWCS
Drugs and Therapeutics Committee
Steve Falk
James Carr
Jeremy Braybrooke
19/07/2013
1.1.a
Version
Document Number
ASWCS11 GI016
Version Number
1.1.a
Last printed 22/07/2011 18:30:00 * 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 18:31:39 +01'00'
Digitally signed by James Carr
DN: cn=James Carr, o=ASWCS, ou=Network
Pharmacist, [email protected], c=GB
Date: 2011.07.22 18:32:02 +01'00'
Digitally signed by Jeremy Braybrooke
DN: cn=Jeremy Braybrooke, o, ou,
[email protected], c=GB
Date: 2011.07.22 18:32:22 +01'00'