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A - Regimen Name

Folinic Acid (Leucovorin)-Fluorouracil-Irinotecan-Aflibercept

Disease Site
Gastrointestinal - Colorectal


Regimen Category
Evidence-Informed :

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 Uses

For the treatment of patients with metastatic colorectal cancer that is resistant to or has progressed following an oxaliplatin-containing regimen.

Irinotecan (individual drug) may be funded for patients with ECOG 0-2 who have not previously received irinotecan for metastatic disease. See NDFP form for details.

B - Drug Regimen

4 mg /kg IV over 1 hour Day 1
(This drug is not currently publicly funded for this regimen and intent)

Followed by:

180 mg /m² IV over 90 minutes Day 1


400 mg /m² IV over 120 minutes concurrently with irinotecan Day 1
400 mg /m² IV bolus, after leucovorin Day 1


2400 mg /m² IV continuous infusion over 46 hours (single dose) Start on Day 1


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. Some studies specified the dose of leucovorin as 200mg/m2 in the l-isomer form. Only the l-isomer is active in the racemic form, thus the dose is 400 mg/m2.

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C - Cycle Frequency


Until disease progression or unacceptable toxicity.

D - Premedication and Supportive Measures

Antiemetic Regimen:


Other Supportive Care:


  • Prophylactic atropine may be considered in patients experiencing cholinergic symptoms, including early diarrhea
  • Diarrhea may be severe and delayed
  • Loperamide 4mg at the onset of diarrhea, then 2mg q2h until patient is diarrhea-free for 12 hours is recommended
E - Dose Modifications

Doses should be modified according to the protocol by which the patient is being treated. The following recommendations have been adapted from clinical trials or product monographs and could be considered.

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 of FOLFIRI 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.

Dosage with toxicity

Aflibercept/FOLFIRI should not be given until neutrophil count is ≥ 1.5 X 109/L and platelet count ≥ 75 x 109/L, and other toxicity has recovered to ≤ grade 2 (or levels specified below).

Aflibercept dose levels: 4 mg/kg, 2 mg/kg

FOLFIRI dose levels: -1 = 15-20% dose reduction

Aflibercept dose modification
FOLFIRI dose modification
Febrile neutropenia or sepsis with neutropenia
No change
↓ irinotecan 1 dose level.
If recurs, also ↓ 5-fluorouracil bolus and infusion by 1 dose level. Consider use of G-CSF.
Hold until recovery. Consider dosage reduction upon restart.
Hold until reaction resolves. Treat with corticosteroids and/or antihistamines. Consider pre-treatment in subsequent cycles; caution as may recur.
Hold until reaction resolves. Treat with corticosteroids and/or antihistamines. Consider pre-treatment in subsequent cycles.
Discontinue if related to aflibercept and treat agressively.
Discontinue if related to FOLFIRI and treat.
Hold for ≥ 4 weeks prior to elective surgery. Restart ≥ 4 weeks after major surgery and until surgical wound is fully healed. May restart once surgical wound is fully healed for minor surgery, biopsy or tooth extraction.
Follow institutional guidelines.
Wound healing issue required intervention
 Hold until recovery and then restart.
mild to moderate
Treat and monitor. If cannot control, hold until controlled. 
If recurs, hold until controlled and restart by ↓ 1 dose level
No change
No change
Toxicity (continued) Severity Aflibercept dose modification FOLFIRI dose modification
Proteinuria ≥ 2 grams/24 hours
Grade 2-3
Hold. Restart when proteinuria < 2 g/ 24 hours.  If recurs, hold until proteinuria < 2 g/ 24 hours and restart by ↓ 1 dose level
No change
Grade 4 (nephrotic syndrome)
No change
Stomatitis and/or hand-foot syndrome
 Grade 3-4
No change
↓ 5-fluorouracil bolus and infusion 1 dose level
 Grade 3-4
No change
Treat with anti-diarrheals and rehydration as required. When recovered to baseline, ↓ irinotecan 1 dose level.
If severe diarrhea recurs, also ↓5-fluorouracil bolus and infusion 1 dose level.
If severe diarrhea persists with both dose reductions, discontinue FOLFIRI.
Venous thromboembolism
Grade 1-3
Treat appropriately and monitor patient. If recurs despite appropriate anticoagulation, discontinue.
Treat appropriately and monitor patient
Grade 4
Discontinue if considered related to FOLFIRI
GI perforation;  Fistula;
Arterial thromboembolism;
Thrombotic microangiopathy;
Cardiotoxicity / decreased LVEF
Any grade

Hepatic Impairment

No dosage adjustment is required for leucovorin. No dosage adjustment is required for aflibercept in mild to moderate hepatic impairment; no data is available in severe hepatic impairment.

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

Renal Impairment

No dosage adjustment is required for leucovorin or aflibercept.

Creatinine Clearance (mL/min)
Fluorouracil (% previous dose)
Irinotecan (% previous dose)
No change No change
 No change
Caution; no data available
 Caution; consider dose ↓
Caution; no data available

Dosage in the Elderly

No dose adjustment required for patients ≥ 65 years of age.  The elderly experienced higher incidences of diarrhea, dizziness, asthenia, decreased weight, and dehydration. Monitor closely for diarrhea and dehydration.

F - Adverse Effects

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

Very common (≥ 50%)

Common (25-49%)

Less common (10-24%)

Uncommon (< 10%),

but may be severe or life-threatening

  • Increased LFTs
  • Nausea, vomiting
  • Fatigue
  • Diarrhea (may be severe)
  • Proteinuria
  • Alopecia
  • Abdominal pain
  • Anorexia
  • Mucositis
  • Hypertension (may be severe)
  • Myelosuppression +/- infection, bleeding (may be severe)
  • Headache
  • Musculoskeletal pain
  • Hand-foot syndrome
  • Dysgeusia
  • Constipation
  • Rash
  • Edema
  • Dizziness
  • Insomnia/somnolence
  • Cough / dyspnea
  • Rhinitis
  • Hypersensitivity
  • GI obstruction, perforation
  • Fistula
  • Pneumonitis, ARDS
  • Renal failure
  • PRES
  • Cardiotoxicity
  • Arterial / venous thromboembolism
  • Delayed wound healing
  • ONJ
  • Thrombotic microangiopathy
  • Secondary malignancy
  • Pancreatitis
  • Tumour lysis sydrome
  • Eye disorders, optic neuritis
  • Ataxia
  • Photosensitivity
G - Interactions

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

Avoid concomitant administration of the following:

  • azole antifungals and other CYP3A4 inhibitors as they increase the risk of irinotecan toxicity
  • prochlorperazine on the same day as irinotecan as akathesia has been observed
  • thiazide diuretics or other drugs that increase the risk of dehydration.


H - Drug Administration and Special Precautions

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



  • Administer as an IV infusion over 1 hour using a 0.2 micron polyethersulfone filter
  • Do not use filters made of polyvinylidene fluoride (PVDF) or nylon
  • DO NOT administer undiluted or as an IV push or bolus
  • NOT for intravitreal injection
  • Dilute in 0.9% sodium chloride USP or 5% dextrose solution for injectio; final concentration of 0.6 to 8 mg/mL


  • 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


  • 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.
  • Leucovorin should not be mixed in the same infusion as 5-fluorouracil as a precipitate may form.
  • Keep refrigerated; protect from light.


  • 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


  • Patients who have a hypersensitivity to aflibercept or any of its components
  • Patients with contraindications to irinotecan, 5-fluorouracil or leucovorin
  • Patients with severe hemorrhage, moderate to severe hepatic impairment, severe myelosuppression or serious infections

Other Warnings/Precautions:

  • Use aflibercept with caution in patients with significant cardiovascular disease as drug-induced hypertension may exacerbate this condition. Aflibercept has not been studied in patients with NYHA class III or IV heart failure. Heart failure has been reported.
  • Compromised wound healing has been observed.  Hold aflibercept for at least 4 weeks prior to elective surgery and do not restart until 4 weeks after surgery (refer to Dosing section).
  • Use with caution when re-treating patients with prior hypersensitivity reactions as recurrent reactions have been observed despite prophylaxis.
  • Use with caution in patients with risk factors for ONJ, including bisphosphonate use.

Pregnancy & lactation:

Aflibercept and FOLFIRI are not recommended for use in pregnancy or breastfeeding.  Adequate contraception should be used by both sexes during treatment, and for at least 6 months after the last dose.

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

  • Blood pressure; baseline and every two weeks or more frequently as clinically indicated
  • CBC with differential count; baseline and prior to each cycle
  • Liver and renal function tests; baseline and before each cycle
  • Urine dipstick; baseline and before each cycle. Patients with dipstick >/= 2+ for protein or urinary protein creatinine ratio (UPCR) > 1 should undergo a 24 hour urine collection
  • LVEF; baseline and as clinically indicated
  • Clinical toxicity assessment of GI effects, bleeding, infection, cardiovascular, thromboembolism, delayed wound healing, respiratory, skin and CNS effects; 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 as clinically indicated

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J - Administrative Information

Approximate Patient Visit
4 hours
Pharmacy Workload (average time per visit)
43.916 minutes
Nursing Workload (average time per visit)
73.333 minutes
K - References

Aflibercept drug monograph, Cancer Care Ontario.

FOLFIRI regimen monograph, Cancer Care Ontario

Van Cutsem E, Tabernero J, Lakomy R, et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol 2012;30(28):3499-506.

August 2019 removed archived PEBC guideline link

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M - Disclaimer

Regimen Abstracts
A Regimen Abstract is an abbreviated version of a Regimen Monograph and contains only top level information on usage, dosing, schedule, cycle length and special notes (if available). It is intended for healthcare providers and is to be used for informational purposes only. It is not intended to constitute or be a substitute for medical advice, and all uses of the Regimen Abstract are subject to clinical judgment. 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, and Cancer Care Ontario disclaims all liability for the use of this information, and for any claims, actions, demands or suits that arise from such use.
Information in regimen abstracts is accurate to the extent of the ST-QBP regimen master listings, and has not undergone the full review process of a regimen monograph.  Full regimen monographs will be published for each ST-QBP regimen as they are developed.
Regimen Monographs
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.
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 information in the Formulary does so at his or her own risk, and by using such information, agrees to indemnify CCO and its content providers from any and all liability, loss, damages, costs and expenses (including legal fees and expenses) arising from such person’s use of the information in the Formulary.