FOLFIRI+CETU

Regimen Monograph

Regimen Name | Drug Regimen | Cycle Frequency | Premedication and Supportive Measures | Dose Modifications | Adverse
Effects | Interactions | Drug Administration and Special Precautions | Recommended Clinical Monitoring | Administrative
Information | References | Other Notes | Disclaimer

A - Regimen Name

FOLFIRI+CETU Regimen
Folinic Acid (Leucovorin)-Fluorouracil-Irinotecan-Cetuximab

Disease Site Gastrointestinal - Colorectal

Intent Palliative

Regimen Evidence-Informed :
Category
Regimen is considered appropriate as part of the standard care of patients;
meaningfully improves outcomes (survival, quality of life), tolerability or costs
compared to alternatives (recommended by the Disease Site Team and
national consensus body e.g. pan-Canadian Oncology Drug Review,
pCODR). Recommendation is based on an appropriately conducted phase III
clinical trial relevant to the Canadian context OR (where phase III trials are not
feasible) an appropriately sized phase II trial. Regimens where one or more
drugs are not approved by Health Canada for any indication will be identified
under Rationale and Use.

Rationale and First-line treatment of EGFR-expressing metastatic colorectal cancer in

Uses patients with wild-type KRAS with an ECOG status of 0-1..

Cetuximab is not indicated in mCRC patients with RAS mutant tumours (exon
2, codons 12, 13; 3, codons 59, 61; or 4, codons 117, 146) or in tumours with
unknown mutation status. Assessment of RAS mutation status should be
performed prior to treatment using a validated test.

Supplementary irinotecan
Public Funding New Drug Funding Program (Irinotecan - First Line - Metastatic Colorectal
Cancer) (NDFP Website)

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B - Drug Regimen

Cetuximab (Loading Dose):

cetuximab 400 mg /m² IV over 2 hours Week 1 ONLY

(This drug is not currently publicly funded for this regimen and intent)

Cetuximab (Maintenance Dose):

cetuximab 250 mg /m² IV over 1 hour Week 2 and then

weekly thereafter
(This drug is not currently publicly funded for this regimen and intent)

in combination with:

irinotecan 180 mg /m² IV over 90 minutes Day 1

leucovorin 1 400 mg /m² IV over 120 minutes Day 1

concurrently with
irinotecan
fluorouracil 400 mg /m² IV bolus, after Day 1
THEN leucovorin

fluorouracil 2400 mg /m²

IV continuous infusion Start on Day 1
over 46 hours (single
dose)
Irinotecan and Leucovorin may be infused at the same time by using a y-connector, but not in the
same bag, then Fluorouracil.

1 Commercially available form is d,l-racemic thus 400 mg/m2. Some studies specified the dose of
leucovorin as 200mg/m2 in the l-isomer (active) formulation.

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C - Cycle Frequency

REPEAT EVERY 14 DAYS

Until disease progression or limited by drug toxicity.

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D - Premedication and Supportive Measures

Antiemetic Regimen: Moderate

Other Supportive Care:

Also refer to CCO Antiemetic Summary

Cetuximab:

An H1 antagonist (e.g. 50 mg of diphenhydramine IV) is recommended with each dose of

cetuximab. Premedication with an intravenous corticosteroid prior to the first dose may be used.

Irinotecan:

Unless contraindicated, atropine 0.25-1mg IV/SC may be given for cholinergic adverse effects
(early diarrhea)
Prophylactic atropine may be considered in patients experiencing cholinergic symptoms
Diarrhea may be severe and delayed with irinotecan; use loperamide 4mg at the onset of
diarrhea, then 2mg q2h until patient is diarrhea-free for 12 hours.

Fluorouracil (5-FU):

May advise patients to suck on ice chips during bolus injection of 5-FU, to reduce stomatitis

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E - Dose Modifications

Doses should be modified according to the protocol by which the patient is being treated.

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Dosage with toxicity

CETUXIMAB

Dose modifications for infusion reactions:

Grade Action Next cycle

Grade1-2 ↓ infusion rate by 50% Use antihistamine
infusion reaction (5mg/min maximum)
Grade 3 or 4 Discontinue immediately Discontinue
infusion reaction
Pneumonitis Hold and investigate Discontinue if confirmed
Keratitis Hold and refer to Consider discontinuation
ophthalmologist

Dose modifications for skin toxicities:

Grade 3 or 4 Rash Action Outcome Cetuximab

1st occurrence Delay infusion Improvement Continue at 250mg/m2
1 to 2 weeks
No Discontinue
improvement
2nd occurrence Delay infusion Improvement Reduce: 200mg/m2
1 to 2 weeks
No Discontinue
improvement
3rd occurrence Delay infusion Improvement Reduce: 150mg/m2
1 to 2 weeks
No Discontinue
improvement
4th occurrence OR Discontinue
any occurrence of
SJS/TENS

FOLFIRI

Patients should not be retreated with irinotecan until recovery from GI toxicity (without loperamide for
at least 24 h) has occurred, platelets ≥ 100 x 109/L, and ANC ≥ 1.5 x 109/L. All dose adjustments
should be based on the worst preceding toxicity.

Patients with ileus, fever or febrile neutropenia should receive antibiotics.

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Do not use in patients with ECOG PS of 3 or 4, nor in patients with moderate or severe increases in
bilirubin.

Consider a reduction in the starting dose described below for elderly patients (≥ 70 years), patients
with prior abdominal or pelvic irradiation, patients with a poor performance status (ECOG of 2),
patients with mild increases in bilirubin (including Gilbert’s syndrome), patients homozygous for
UGT1A1*28 allele or patients with a history of myelosuppression with previous treatment.

Suggested Dose Levels:

Regimen Drug Starting Dose level -1 Dose Level -2
dose (mg/m ) (mg/m2)
2 (mg/m2)
FOLFIRI Irinotecan 180 150 120
Leucovorin infusion 400 No change No change
5-FU bolus 400 320 240

5-FU infusion 2400 2000 1600

(start day 1 over
46h*)
* This 5-FU dosing is not approved by Health Canada, but has been used in some phase III trials.

Dosage with Toxicity

At the start of subsequent cycles1, 2
Toxicity Grade

Hematologic
No change
Grade 1
No change
Grade 2
↓ 1 dose level
Grade 3
Grade 4 or febrile ↓ 2 dose levels
neutropenia
Diarrhea
2-3/day > pre-treatment No change
4-6/day > pre-treatment No change
7-9/day > pre-treatment ↓ 1 dose level
≥ 10/day > pre-treatment ↓ 2 dose levels
1 Relative to the starting dose used in the previous cycle.
2 Patients should not be retreated until GI toxicity resolved (without loperamide for at least 24 h),
platelets ≥ 100 x 109/L, and ANC ≥ 1.5 x 109/L. If no recovery after a 2-week delay, consider
discontinuing treatment.

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Hepatic Impairment

The safety and efficacy of cetuximab have not been studied in patients with hepatic impairment. No
dose adjustment required for leucovorin. OMIT leucovorin if 5-FU is omitted.

Transaminases Bilirubin Irinotecan Fluorouracil

1-1.5 X ULN Consider ↓ No change
> 3 X ULN* 2-4 X ULN Omit No change
> 4 XULN Omit Omit
* or 5 X ULN with liver metastases

Renal Impairment

The safety and efficacy of cetuximab have not been studied in patients with renal impairment.
No dose adjustment required for leucovorin.

Creatinine Clearance Fluorouracil (% Irinotecan (% previous

(mL/min) previous dose) dose)
>60 No change No change
30-60 No change Caution; no data available
<30 Caution; consider dose ↓ Caution; no data available

Dosage in the Elderly

No dosage adjustment is required for cetuximab. Elderly patients receiving irinotecan may be at
increased risk of diarrhea and should be monitored closely. Consider reducing the irinotecan
starting dose in patients aged 70 and older.

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F - Adverse Effects

Refer to cetuximab, irinotecan, leucovorin, fluorouracil drug monograph(s) for additional details of
adverse effects

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Very common (≥ Common (25-49%) Less common (10- Uncommon (< 10%),
50%) 24%)
but may be severe or
life-threatening
Rash (may Neuropathy Hand-foot Arterial / venous
be severe) Cough, dyspnea syndrome thromboembolism
Fatigue Hypomagnesemia Dizziness Arrhythmia
Increased Infection (may be Musculoskeletal Cardiotoxicity
LFTs (may severe) pain GI obstruction /
be severe) Headache Paronychia perforation
Nausea, Mucositis Infusion Hypersensitivity
vomiting Insomnia reaction Pancreatitis
Anorexia Myelosuppression +/- Mood changes Pneumonitis
Alopecia bleeding, Rhinitis Renal failure
Abdominal infection (may be Dry mouth Keratitis, optic
pain severe) Edema neuritis
Constipation Nail disorders Somnolence Tumour lysis
Diarrhea syndrome
(may be Hemolysis
severe)
EKG
changes

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G - Interactions

Refer to cetuximab, irinotecan, leucovorin, fluorouracil drug monograph(s) for additional details

Additive skin toxicity may occur when cetuximab is given in combination with radiation
Monitor drug levels and toxicity with phenytoin
Monitor INR levels and toxicity with warfarin
Azole antifungals are contraindicated with irinotecan (discontinue one week before the first
dose of irinotecan)
Avoid concomitant use of strong CYP3A4 inhibitors and inducers with irinotecan
Avoid concomitant use of prochlorperazine, turmeric and azatanavir with irinotecan

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H - Drug Administration and Special Precautions

Refer to cetuximab, irinotecan, leucovorin, fluorouracil drug monograph(s) for additional details

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Administration:

Cetuximab:

Do not shake or further dilute the solution.

DO NOT ADMINISTER AS AN IV PUSH OR BOLUS.
Transfer undiluted solution into an empty Viaflex bag or an empty syringe, if using a syringe
pump.
Administer the undiluted solution via a low protein binding 0.22-micrometer in-line filter.
Piggybacking to the patient’s infusion line, infuse initial loading dose over 2 hours, and
maintenance dose over 1 hour (maximum rate 10 mg/min). (May require infusion at slower rate
in those who experienced infusion reactions).
Prime administration line with drug solution before infusion and may use NS to flush line at the
end of infusion.
A 1-hour observation period is recommended following each cetuximab infusion. Longer
observation periods may be required in those who experienced infusion reactions.
Should not be mixed or diluted with other drugs.
Discard any unused portion left in a vial 12 hours under refrigeration or 8 hours at room
temperature, as the product contains no preservatives.

Irinotecan:

Mix in 500mL bag (D5W-preferred or NS) in a concentration range between 0.12 to 3 mg/mL;
infuse IV over 90 minutes
Do not refrigerate admixtures in NS (may result in precipitation)
Avoid freezing irinotecan and its admixtures since this may result in drug precipitation.
Do not admix with other drugs
Protect from light
Prior to the initial irinotecan treatment, patients should be given a sufficient supply of
loperamide and instructed on its appropriate use.
Avoid grapefruit, starfruit, Seville oranges, their juices or products during irinotecan treatment

Leucovorin:

Doses ≤100mg may be given by IV push through sidearm of free flowing IV (5% Dextrose,
Normal Saline or 2/3-1/3). The injection must not exceed 160mg/min of leucovorin (due to
calcium content).
May be mixed in 50mL Normal Saline or 5% Dextrose minibag (doses up to 500mg) or
100mL minibag (doses >500mg) or in 100mL fluid in graduated administration set (5%
Dextrose, Normal Saline or 2/3-1/3); Give over 15 minutes.
Continuous infusion using CADD pump or similar device.
Cryodesiccated powder reconstituted with Bacteriostatic Water for Injection containing benzyl
alcohol should only be used at doses below 10 mg/m2
Leucovorin should not be mixed in the same infusion as 5-fluorouracil as a precipitate may
form.
Keep refrigerated; protect from light.

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Fluorouracil:

IV PUSH OR INTERMITTENT INFUSION:

Slow push through sidearm of free-flowing IV (5% Dextrose, Normal Saline)
May be mixed in 50mL minibag (NS or D5W); infuse over 15 min.
Protect from light.
IV CONTINUOUS INFUSION:
Continuous infusion using CADD infusion pump, or similar device
Infuse through central venous access device, if available
Infusion volume and duration depend on protocol.
Protect from light
Infuse through patent peripheral venous catheter, if infusion for only 3-5 days; Inspect
peripheral infusion sites daily and replace if evidence of irritation or extravasation
Incompatible with doxorubicin, epirubicin, diazepam, methotrexate and cytarabine; line must
be flushed between administrations of fluorouracil and these agents

Contraindications:

Patients with known hypersensitivity to cetuximab, murine protein or any components of the
product or FOLFIRI regimen
Treatment of colorectal cancer in patients with K-RAS mutations or K-RAS unknown status
Patients with ECOG performance status of 3 or 4
Patients with moderate to severe hepatic dysfunction
Avoid FOLFIRi in patients with hereditary fructose or glucose-galactose or lactose intolerance
Avoid the use of live or live attenuated vaccines
Leucovorin should be avoided in the treatment of pernicious anemia or vitamin B12 deficiency
anemias
Leucovorin contraindicated for intrathecal use
Patients with depressed bone marrow function (prior pelvic irradiation / marrow infiltration)
Patients with potentially serious infections

Other warnings/precautions:

Patients with a history of, or pre-existing keratitis, dry eyes or contact lens use
Patients with poor performance status, or cardiopulmonary disease are at increased risk of
severe hypersensitivity
Elderly patients, patients with poor performance status (= 2), limited marrow reserve, 3rd
space accumulation, Gilbert’s syndrome and patients with reduced UGT1A1 activity may be
more susceptible to the toxic effects of irinotecan; they should be carefully monitored and dose
reduction considered
Use fluorouracil with extreme caution in patients who have undergone recent major surgery,
with renal or hepatic impairment, widespread bone marrow involvement, or are suspected to
have DPD deficiency
This regimen is not recommended for use in pregnancy. Adequate contraception should be
used by both sexes during treatment, and for at least 6 months after the last dose.
Breastfeeding is not recommended.

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I - Recommended Clinical Monitoring

Treating physicians may decide to monitor more or less frequently for individual patients but should
always consider recommendations from the product monograph.

Recommended Clinical Monitoring

CBC, liver and renal function tests; baseline and at each visit
Electrolytes, including serum magnesium, potassium and calcium; baseline, at each
visit and monthly for 2 months following completion of therapy
Clinical toxicity assessment for infection, bleeding, skin, nail, cardiac,
thromboembolism, GI, respiratory effects, hypersensitivity and fatigue; at each visit

Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for
Adverse Events) version

Suggested Clinical Monitoring

Blood glucose, especially in patients with diabetes; baseline and at each visit

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J - Administrative Information

Pharmacy Workload (average time per visit) 51.753 minutes

Nursing Workload (average time per visit) 86.5 minutes

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K - References

André T, Louvet C, Maindrault-Goebel F, et al: CPT-11 (irinotecan) addition to bimonthly, high-dose

leucovorin and bolus and continuous-infusion 5-fluorouracil (FOLFIRI) for pretreated metastatic
colorectal cancer. GERCOR. Eur J Cancer 35:1343-1347, 1999.

Cetuximab drug monograph, Cancer Care Ontario.

Douillard JY, Cunningham D, Roth AD et al. Irinotecan combined with fluorouracil compared with
fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomized
trial. The Lancet, March 2000; 355: 1041-47.

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FOLFIRI regimen monograph, Cancer Care Ontario.

Van Cutsem E, Kohne C-H, Hitre E et al. Cetuximab and chemotherapy as initial treatment for
metastatic colorectal cancer. N Engl J Med 2009;360:1408-17.

Van Cutsem E et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatmentfor
metastatic colorectal cancer: updated analysis of overall survival according to tumor K-ras and
BRAF mutation status. J Clin Oncol 2011;29(15):2011-2019.

PEBC Advice Documents or Guidelines

The Use of Leucovorin in Colorectal Cancer

June 2017 added not publicly funded to drug regimen (cetuximab)

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M - Disclaimer

Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public
funding information.

The information set out in the drug monographs, regimen monographs, appendices and symptom management
information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare
providers and is to be used for informational purposes only. The information is not intended to cover all possible uses,
directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate
that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is
not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All
uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information
provided in the Formulary.

The format and content of the drug monographs, regimen monographs, appendices and symptom management
information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of
last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly
evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended
that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.

Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom
management information (for patients), are intended for patients. Patients should always consult with their healthcare
provider if they have questions regarding any information set out in the Formulary documents.

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While care has been taken in the preparation of the information contained in the Formulary, such information is
provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory
or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability.

CCO and the Formulary’s content providers shall have no liability, whether direct, indirect, consequential, contingent,
special, or incidental, related to or arising from the information in the Formulary or its use thereof, whether based on
breach of contract or tort (including negligence), and even if advised of the possibility thereof. Anyone using the
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and its content providers from any and all liability, loss, damages, costs and expenses (including legal fees and
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