NCCP National SACT Regimen

FOLFOX-4 Therapy-14 day

INDICATIONS FOR USE:
Regimen Reimbursement
INDICATION ICD10 Code Status
Adjuvant treatment of stage II or III colon cancer after complete C18 00210a Hospital
resection of primary tumour
Metastatic colorectal carcinoma C18 00210b Hospital

TREATMENT:
The starting dose of the drugs detailed below may be adjusted downward by the prescribing clinician, using their
independent medical judgement, to consider each patients individual clinical circumstances.

Adjuvant treatment is administered every 14 days for 12 cycles or until disease progression or unacceptable
toxicity develops.

For metastatic colon carcinoma, treatment is administered continuously or until disease progression or
unacceptable toxicity develops.

Facilities to treat anaphylaxis MUST be present when systemic anti-cancer therapy (SACT) is administered.

Order
of Day Drug Dose Route Diluent & Rate Cycle
Admin
1 1 Oxaliplatin a 85mg/m2 IV infusion 500ml glucose 5% over 2hrs Every 14 days

2 1 Folinic Acid b 200mg/m2 IV infusion 250ml glucose 5% over 2hrs Every 14 days
(Calcium
leucovorin)
3 1 and 2 5-Fluorouracil 400mg/m2 IV BOLUS Every 14 days

4 1 and 2 5-Fluorouracilc 600mg/m2 Continuous Over 22h in 0.9% NaCl. Every 14 days
IV infusion
a Oxaliplatinis incompatible with 0.9% NaCl. Do not piggyback or flush lines with normal saline.
For oxaliplatin doses ≤ 104mg use 250ml glucose 5%.
Increase infusion rate time to 4 – 6 hours in case of laryngopharyngeal dysaesthesia reaction.
Oxaliplatin administration must always precede the administration of 5-Fluorouracil.
Oxaliplatin may be given at the same time as Folinic Acid (Calcium Leucovorin) using a Y connector.

b Folinic
Acid (Calcium Leucovorin) must be administered prior to 5-Fluorouracil. It enhances the effects of 5-Fluorouracil by increasing 5-
Fluorouracil binding to the target enzyme thymidylate synthetase.

Acute neurotoxicity is common with oxaliplatin and can be precipitated on exposure to the cold therefore in this regimen patients should NOT
suck on ice chips during the bolus injection of fluorouracil.
c See dose modifications section for patients with identified partial dihydropyrimidine dehydrogenase (DPD) deficiency.

Published: 10/01/2015
NCCP Regimen: FOLFOX-4-14 day Version number: 9a
Review: 18/11/2026
Tumour Group: Gastrointestinal ISMO Contributor: Prof Maccon Keane
Page 1 of 7
NCCP Regimen Code: 00210
The information contained in this document is a statement of consensus of NCCP and ISMO or IHS professionals regarding their views of currently accepted
approaches to treatment. Any clinician seeking to apply or consult these documents is expected to use independent medical judgement in the context of
individual clinical circumstances to determine any patient's care or treatment. Use of these documents is the responsibility of the prescribing clinician and is
subject to HSE’s terms of use available at http://www.hse.ie/eng/Disclaimer
This information is valid only on the day of printing, for any updates please check www.hse.ie/NCCPchemoregimens
 NCCP National SACT Regimen

ELIGIBILITY:
 Indications as above
 ECOG 0-2
 Adequate haematological, renal and liver status

CAUTION:
Use with caution in patients with
 Previous pelvic radiotherapy
 Recent MI
 Uncontrolled angina, hypertension, cardiac arrhythmias, congestive heart failure (CHF)
 In patients with baseline greater than 3 loose bowel movements (BM) per day (in patients
without colostomy or ileostomy)
 Symptomatic peripheral neuropathy

EXCLUSIONS:
 Hypersensitivity to oxaliplatin, 5-Fluorouracil, folinic acid or any of the excipients
 Severe renal impairment (creatinine clearance < 30ml/min)
 Breast feeding
 Peripheral neuropathy with functional impairment prior to first cycle
 Known complete dihydropyrimidine dehydrogenase (DPD) deficiency

PRESCRIPTIVE AUTHORITY:
The treatment plan must be initiated by a Consultant Medical Oncologist.

TESTS:

Baseline tests:
 FBC, liver and renal profile
 ECG (if patient has compromised cardiac function)
 DPD testing prior to first treatment with 5-Fluorouracil using phenotype and/or genotype testing
unless patient has been previously tested

Regular tests:
 FBC, liver and renal profile prior to each cycle
 Evaluate for peripheral neuropathy every 2 cycles

Disease monitoring:
Disease monitoring should be in line with the patient’s treatment plan and any other test/s as directed
by the supervising Consultant.

Published: 10/01/2015
NCCP Regimen: FOLFOX-4-14 day Version number: 9a
Review: 18/11/2026
Tumour Group: Gastrointestinal ISMO Contributor: Prof Maccon Keane
Page 2 of 7
NCCP Regimen Code: 00210
The information contained in this document is a statement of consensus of NCCP and ISMO or IHS professionals regarding their views of currently accepted
approaches to treatment. Any clinician seeking to apply or consult these documents is expected to use independent medical judgement in the context of
individual clinical circumstances to determine any patient's care or treatment. Use of these documents is the responsibility of the prescribing clinician and is
subject to HSE’s terms of use available at http://www.hse.ie/eng/Disclaimer
This information is valid only on the day of printing, for any updates please check www.hse.ie/NCCPchemoregimens
 NCCP National SACT Regimen

DOSE MODIFICATIONS:
 Consider a reduced starting dose in patients with identified partial DPD deficiency
o Initial dose reduction may impact the efficacy of treatment
o In the absence of serious toxicity, subsequent doses may be increased with careful monitoring.
 Any dose modification should be discussed with a Consultant
 The following dose reductions should be used when calculating FOLFOX dose reductions for patients
with toxicities

Table 1: Dose Reduction Levels for All Toxicity

Dose Level 0 Dose Level -1 Dose Level -2 Dose Level -3
Oxaliplatin 85 mg/m2 65 mg/m2 50 mg/m2 Discontinue
Folinic Acid 200 mg/m2 200 mg/m2 200 mg/m2 Discontinue
(Calcium
Leucovorin)
5-Fluorouracil 400 mg/m2 320 mg/m2 260 mg/m2 Discontinue
bolus
5-Fluorouracil 600 mg/m2 500 mg/m2 400 mg/m2 Discontinue
infusion
Note: Folinic acid is delayed or omitted if bolus 5-Fluorouracil is delayed or omitted

Haematological:
Table 2. Dose Modifications for Haematological Toxicity
TOXICITY Dose Level for Subsequent Cycles
Prior to a Cycle (DAY 1) Grade ANC Oxaliplatin 5-Fluorouracil
(x109/L)
 If ANC< 1.5 on Day 1 of cycle, hold 1 ≥ 1.5 Maintain dose Maintain dose
treatment, weekly FBC, maximum level level
of 4 weeks 2 1.0-1.49 Maintain dose Maintain dose
 ANC ≥ 1.5 within 4 weeks, proceed level level
with treatment at the dose level 3 0.5-0.99  1 dose level Maintain dose
noted across from the lowest ANC level
result of the delayed week(s). 4 <0.5  1 dose level Omit bolus and
 If ANC remains <1.5 after 4 weeks 1 infusion dose
discontinue treatment level

Grade Platelets Oxaliplatin 5-Fluorouracil

(x109/L)
 If platelets < 75 on Day 1 of cycle, 1 ≥ 75 Maintain dose Maintain dose
hold treatment, weekly FBC, level level
maximum of 4 weeks 2 50-74.9 Maintain dose Maintain dose
 Platelets ≥ 75 within 4 weeks, level level
proceed with treatment at the  Maintain dose
dose level noted across from the 3 10-49.9  1 dose level level
lowest platelets result of the 
delayed week(s). 
 If platelets remain <75 after 4  Maintain dose
weeks discontinue treatment 4 <10  2 dose levels level

Published: 10/01/2015
NCCP Regimen: FOLFOX-4-14 day Version number: 9a
Review: 18/11/2026
Tumour Group: Gastrointestinal ISMO Contributor: Prof Maccon Keane
Page 3 of 7
NCCP Regimen Code: 00210
The information contained in this document is a statement of consensus of NCCP and ISMO or IHS professionals regarding their views of currently accepted
approaches to treatment. Any clinician seeking to apply or consult these documents is expected to use independent medical judgement in the context of
individual clinical circumstances to determine any patient's care or treatment. Use of these documents is the responsibility of the prescribing clinician and is
subject to HSE’s terms of use available at http://www.hse.ie/eng/Disclaimer
This information is valid only on the day of printing, for any updates please check www.hse.ie/NCCPchemoregimens
 NCCP National SACT Regimen

Renal and Hepatic Impairment:

Table 3: Dose modification in renal or hepatic impairment
Drug Renal impairment Hepatic impairment
Oxaliplatin CrCl Dose Little information available.
(ml/min) Probably no dose reduction necessary. Clinical decision.
>30 Treat at normal
dose and monitor
renal function
<30 Contraindicated
5-Fluorouracil Consider dose reduction in Bilirubin (micromol/L) AST Dose
severe renal impairment only
<85 <180 100%
>85 or >180 Contraindicated
Clinical decision.
Moderate hepatic impairment; reduce initial dose by 1/3.
Severe hepatic impairment, reduce initial dose by 1/2.
Increase dose if no toxicity.

Management of adverse events:

Table 4: Dose modification schedule based on adverse events
Adverse reactions Recommended dose modification
*Peripheral neuropathy
Grade 2 present at start of cycle Reduce oxaliplatin by 1 dose level
Grade 3
 First occurrence  1 dose level
 2nd occurrence  1 dose level
 Persistent Discontinue oxaliplatin
Grade 4 Discontinue oxaliplatin
Laryngopharyngeal dysaesthesia Increase infusion time from 2 to 6 hrs
Stomatitis Delay treatment until stomatitis reaches level of grade 1 or
less
Grade 4 Diarrhoea In adjuvant treatment reduce oxaliplatin dose to 75mg/m2 and
in metastatic treatment reduce oxaliplatin dose to 65mg/m 2 in
addition to any 5-Fluorouracil dose reductions required.
Unexplained respiratory symptoms e.g. Discontinue oxaliplatin until interstitial disease or pulmonary
Non-productive cough, dyspnoea, crackles fibrosis excluded.
or radiological pulmonary infiltrates
*Neuropathy may be partially or wholly reversible after discontinuation of therapy; patients with good recovery from Grade 3 (not Grade 4)
neuropathy may be considered for re- challenge with oxaliplatin, with starting dose one level below that which they were receiving when
neuropathy developed.

Published: 10/01/2015
NCCP Regimen: FOLFOX-4-14 day Version number: 9a
Review: 18/11/2026
Tumour Group: Gastrointestinal ISMO Contributor: Prof Maccon Keane
Page 4 of 7
NCCP Regimen Code: 00210
The information contained in this document is a statement of consensus of NCCP and ISMO or IHS professionals regarding their views of currently accepted
approaches to treatment. Any clinician seeking to apply or consult these documents is expected to use independent medical judgement in the context of
individual clinical circumstances to determine any patient's care or treatment. Use of these documents is the responsibility of the prescribing clinician and is
subject to HSE’s terms of use available at http://www.hse.ie/eng/Disclaimer
This information is valid only on the day of printing, for any updates please check www.hse.ie/NCCPchemoregimens
 NCCP National SACT Regimen

SUPPORTIVE CARE:

EMETOGENIC POTENTIAL:
Oxaliplatin: Moderate (Refer to local policy).
5-Fluorouracil: Low (Refer to local policy).

PREMEDICATIONS: Not usually required unless the patient has had a previous
hypersensitivity.OTHER SUPPORTIVE CARE: Anti-diarrhoeal treatment (Refer to local policy).

ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS:

The adverse effects listed are not exhaustive. Please refer to the relevant Summary of Product Characteristics for full
details.
 Platinum Hypersensitivity: Special surveillance should be ensured for patients with a history of allergic
manifestations to other products containing platinum. In case of anaphylactic manifestations, the
infusion should be interrupted immediately and an appropriate symptomatic treatment started. Re-
administration of oxaliplatin to such patients is contraindicated.
 Laryngopharyngeal dysesthesia: An acute syndrome of laryngopharyngeal dysesthesia occurs in 1-2% of
patients and is characterised by subjective sensations of dysphagia or dyspnoea/feeling of suffocation,
without any objective evidence of respiratory distress (no cyanosis or hypoxia) or of laryngospasm or
bronchospasm. Symptoms are often precipitated by exposure to cold. Although antihistamines and
bronchodilators have been administered in such cases, the symptoms are rapidly reversible even in the
absence of treatment. Prolongation of the infusion helps to reduce the incidence of this syndrome.
 Gastrointestinal toxicity: Patients treated with 5-Fluorouracil should be closely monitored for diarrhoea
and managed appropriately.
 Neutropenia: Fever or other evidence of infection must be assessed promptly and treated aggressively.
 Myocardial ischaemia and angina: Cardiotoxicity is a serious complication during treatment with 5-
Fluorouracil. Patients, especially those with a prior history of cardiac disease or other risk factors, treated
with 5-Fluorouracil, should be carefully monitored during therapy.
 DPD deficiency: DPD is an enzyme encoded by the DPYD gene, which is responsible for the breakdown
of fluoropyrimidines. Patients with DPD deficiency are therefore at increased risk of fluoropyrimidine-
related toxicity, including for example stomatitis, diarrhoea, mucosal inflammation, neutropenia and
neurotoxicity. Treatment with 5-Fluorouracil, capecitabine or tegafur-containing medicinal products is
contraindicated in patients with known complete DPD deficiency. Consider a reduced starting dose in
patients with identified partial DPD deficiency. Initial dose reduction may impact the efficacy of
treatment. In the absence of serious toxicity, subsequent doses may be increased with careful monitoring.
Therapeutic drug monitoring (TDM) of 5-Fluorouracil may improve clinical outcomes in patients receiving
continuous 5-Fluorouracil infusions.
 Extravasation: Oxaliplatin causes irritation if extravasated (Refer to local policy).
 Venous occlusive disease: A rare but serious complication that has been reported in patients (0.02%)
receiving oxaliplatin in combination with 5-Fluorouracil. This condition can lead to hepatomegaly,
splenomegaly, portal hypertension and/or esophageal varices. Patients should be instructed to report
any jaundice, ascites or haematemesis immediately.

Published: 10/01/2015
NCCP Regimen: FOLFOX-4-14 day Version number: 9a
Review: 18/11/2026
Tumour Group: Gastrointestinal ISMO Contributor: Prof Maccon Keane
Page 5 of 7
NCCP Regimen Code: 00210
The information contained in this document is a statement of consensus of NCCP and ISMO or IHS professionals regarding their views of currently accepted
approaches to treatment. Any clinician seeking to apply or consult these documents is expected to use independent medical judgement in the context of
individual clinical circumstances to determine any patient's care or treatment. Use of these documents is the responsibility of the prescribing clinician and is
subject to HSE’s terms of use available at http://www.hse.ie/eng/Disclaimer
This information is valid only on the day of printing, for any updates please check www.hse.ie/NCCPchemoregimens
 NCCP National SACT Regimen

 Haemolytic Ureamic Syndrome (HUS): Oxaliplatin therapy should be interrupted if HUS is suspected:
hematocrit is less than 25%, platelets less than 100,000 and creatinine greater than or equal to 135
micromol/L. If HUS is confirmed, oxaliplatin should be permanently discontinued.
 Hand-foot syndrome (HFS), also known as palmar-plantar erythrodysaesthesia (PPE) has been reported
as an unusual complication of high dose bolus or protracted continuous therapy for 5-Fluorouracil.

DRUG INTERACTIONS:
 Marked elevations of prothrombin time and INR have been reported in patients stabilized on warfarin
therapy following initiation of 5-Fluorouracil regimens.
 Concurrent administration of 5-Fluorouracil and phenytoin may result in increased serum levels of
phenytoin.
 5-Fluorouracil is contraindicated in combination with brivudin, sorivudin and analogues as these are
potent inhibitors of the 5-Fluorouracil-metabolising enzyme DPD.
 Caution should be taken when using 5-Fluorouracil in conjunction with medications which may affect DPD
activity.
 Current drug interaction databases should be consulted for more information.

REFERENCES:
1. André T, Boni C et al. Oxaliplatin, Fluorouracil, and Leucovorin as Adjuvant Treatment for Colon Cancer.
N Engl J Med 2004; 350:2343-2351.
2. De Gramont A., A. Figer, M. Seymour, et al. Leucovorin and fluorouracil with or without oxaliplatin as
first- line treatment in advanced colorectal cancer. J.Clin Oncol 2000; 18: 2938-2947.
3. Krens S D, Lassche,Jansman G F G A, et al. Dose recommendations for anticancer drugs in patients
with renal or hepatic impairment. Lancet Onco/2019 20:e201-08.
4. Dosage Adjustment for Cytotoxics in Renal Impairment January 2009; North London Cancer Network.
5. Dosage Adjustment for Cytotoxics in Hepatic Impairment January 2009; North London Cancer Network.
6. NCCP Classification Document for Systemic Anti-Cancer Therapy (SACT) Induced Nausea and Vomiting.
V3 2021. Available at: https://www.hse.ie/eng/services/list/5/cancer/profinfo/chemoprotocols/nccp-
classification-document-for-systemic-anti-cancer-therapy-sact-induced-nausea-and-vomiting.pdf
7. HPRA Direct Healthcare Professional Communication. 5-Fluorouracil (i.v.), capecitabine and tegafur
containing products: Pre-treatment testing to identify DPD-deficient patients at increased risk of severe
toxicity. Accessed Aug 2020 Available at: https://www.hpra.ie/docs/default-source/default-document-
library/important-safety-information-from-marketing-authorisation-holders-of-products-containing-5-
fluorouracil-(i-v-)-capecitabine-and-tegafur-as-approved-by-the-hpra.pdf?sfvrsn=0
8. Oxaliplatin (Eloxatin®) Summary of Product Characteristics. Last updated: 23/04/2019. Accessed Nov
2021. Available at: https://www.hpra.ie/img/uploaded/swedocuments/Licence_PA0540-148-
001_23042019151332.pdf
9. Fluorouracil 50 mg/ml solution. Summary of Product Characteristics. Last updated: 16/04/2021.
Accessed Nov 2021. Available at: https://www.hpra.ie/img/uploaded/swedocuments/Licence_PA2315-
091-001_16042021165722.pdf

Published: 10/01/2015
NCCP Regimen: FOLFOX-4-14 day Version number: 9a
Review: 18/11/2026
Tumour Group: Gastrointestinal ISMO Contributor: Prof Maccon Keane
Page 6 of 7
NCCP Regimen Code: 00210
The information contained in this document is a statement of consensus of NCCP and ISMO or IHS professionals regarding their views of currently accepted
approaches to treatment. Any clinician seeking to apply or consult these documents is expected to use independent medical judgement in the context of
individual clinical circumstances to determine any patient's care or treatment. Use of these documents is the responsibility of the prescribing clinician and is
subject to HSE’s terms of use available at http://www.hse.ie/eng/Disclaimer
This information is valid only on the day of printing, for any updates please check www.hse.ie/NCCPchemoregimens
 NCCP National SACT Regimen

Version Date Amendment Approved By

1 10/1/2015 Prof Maccon Keane
2 24/2/2015 Infusor table update Prof Maccon Keane
3 01/03/2017 Reviewed Prof Maccon Keane
4 4/10/2017 Updated with new NCCP regimen template and Prof Maccon Keane
updated dosing in haematological toxicity
5 09/10/2019 Reviewed. Standardisation of treatment table. Prof Maccon Keane
Updated exclusions, dose modifications, drug
interactions, emetogenic potential.
6 09/01/2020 Updated recommended dose modifications for Prof Maccon Keane
oxaliplatin in renal impairment.
updated infusion fluids for Folinic Acid (Calcium
leucovorin) Updated exclusion criteria for DPD.
7 26/02/2020 Standardisation of treatment table Prof Maccon Keane
8 20/08/2020 Updated exclusion criteria, baseline testing, dose Prof Maccon Keane
modifications and adverse events with respect to
DPD deficiency as per DHPC from HPRA June 2020
Updated Adverse events regarding palmar-plantar
erythrodysaesthesia

9 18/11/2021 Reviewed. Updated Exclusions. Prof Maccon Keane

9a 21/11/2023 Formatting changes and grammatical corrections. NCCP

Comments and feedback welcome at oncologydrugs@cancercontrol.ie

Published: 10/01/2015
NCCP Regimen: FOLFOX-4-14 day Version number: 9a
Review: 18/11/2026
Tumour Group: Gastrointestinal ISMO Contributor: Prof Maccon Keane
Page 7 of 7
NCCP Regimen Code: 00210
The information contained in this document is a statement of consensus of NCCP and ISMO or IHS professionals regarding their views of currently accepted
approaches to treatment. Any clinician seeking to apply or consult these documents is expected to use independent medical judgement in the context of
individual clinical circumstances to determine any patient's care or treatment. Use of these documents is the responsibility of the prescribing clinician and is
subject to HSE’s terms of use available at http://www.hse.ie/eng/Disclaimer
This information is valid only on the day of printing, for any updates please check www.hse.ie/NCCPchemoregimens