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FOLFIRI+BEVA; FOLFIRI

Cancer Type: Gastrointestinal, Colorectal, Small bowel and appendix  Intent: Palliative
Regimen Category: Evidence-Informed
Funding:
New Drug Funding Program
    Irinotecan - First Line - Metastatic Colorectal Small Bowel or Appendiceal Cancer
New Drug Funding Program
    Irinotecan - Second Line - Metastatic Colorectal Small Bowel or Appendiceal Cancer
New Drug Funding Program
    Bevacizumab (Biosimilar) - First Line - Metastatic Colorectal, Small Bowel, or Appendiceal Cancer
A - Regimen Name

FOLFIRI Regimen
Folinic Acid (Leucovorin)-Fluorouracil-Irinotecan
FOLFIRI+BEVA Regimen
Folinic Acid (Leucovorin)-Fluorouracil-Irinotecan-Bevacizumab


Disease Site
Gastrointestinal - Colorectal
Gastrointestinal - Small bowel and appendix

Intent
Palliative

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

FOLFIRI:  First-line and second-line treatment of metastatic colorectal, small bowel or appendiceal cancer
FOLFIRI+BEVA:  First-line treatment of metastatic colorectal, small bowel or appendiceal cancer


Supplementary Public Funding

irinotecan
New Drug Funding Program (Irinotecan - First Line - Metastatic Colorectal Small Bowel or Appendiceal Cancer)

irinotecan
New Drug Funding Program (Irinotecan - Second Line - Metastatic Colorectal Small Bowel or Appendiceal Cancer)

bevacizumab
New Drug Funding Program (Bevacizumab (Biosimilar) - First Line - Metastatic Colorectal, Small Bowel, or Appendiceal Cancer)

 
B - Drug Regimen

Different bevacizumab products are not interchangeable.
 

irinotecan
180 mg /m² IV over 90 minutes Day 1
leucovorin
1
400 mg /m² IV over 120 minutes concurrently with irinotecan Day 1
fluorouracil
400 mg /m² IV bolus, after leucovorin Day 1
THEN
fluorouracil
2
2400 mg /m² IV continuous infusion over 46 hours only Start on Day 1
with or without:
bevacizumab

3, 4

5 mg /kg IV over 90 minutes for initial dose 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.
1Commercially available form is d,l-racemic. Some studies specified the dose of leucovorin as 200mg/m² in the l-isomer form. Since only the l-isomer is active in the racemic form, thus the dose is doubled.
2 Dose may be escalated to 3000 mg/m² if toxicity ≤ grade 1 during the first two cycles.
3 If tolerated, next infusion can be given over 60 minutes; can thereafter be given over 30 minutes as maintenance dose.   Alternative administration rates have been described by Mahfoud et al and Reidy et al, but these have not been approved by Health Canada.
4 Sequence of administration:  Bevacizumab has been given prior to chemotherapy in several phase III clinical trials. 

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C - Cycle Frequency

REPEAT EVERY 14 DAYS

Until evidence of disease progression or unacceptable toxicity

 
D - Premedication and Supportive Measures

Antiemetic Regimen:

Moderate

Other Supportive Care:

  • Irinotecan:
  • Unless contraindicated, atropine 0.25-1mg IV/SC may be used for cholinergic adverse effects (early diarrhea)
  • Diarrhea (abdominal cramp = 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
  • Patients with ileus, fever or febrile neutropenia should receive antibiotics
  • 5FU:
  • May advise patients to suck on ice chips during bolus injection of 5FU, to reduce stomatitis

Also refer to CCO Antiemetic Summary

 
E - Dose Modifications

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

Refer to bevacizumab drug monograph for additional details on bevacizumab.

 

Dosage with toxicity

See general recommendations for hematologic toxicity.

FOLFIRI

Patients should not be re-treated with irinotecan until recovery (to baseline) from GI toxicity (without loperamide for at least 24 hours) 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.

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 (mg/m2)
Dose level -1 (mg/m2)
Dose Level -2 (mg/m2)
FOLFIRI
 
 
Irinotecan
180
150
120
Leucovorin infusion
400
No change
No change
5-FU bolus
 
400
320
240
5-FU infusion
(start day 1 over 46h*)
2400
2000
1600

 * This 5-FU dosing is not approved by Health Canada, but has been used in some phase III trials.

 

Dosage with Toxicity:

Dose Adjustments for Irinotecan in Combination with Fluorouracil:

Worst Toxicity Grade from Previous Cycle

At the start of subsequent cycles1, 2       (FOLFIRI)

 Hematologic 

 Grade 1

No change

Grade 2

No change

Grade 3

reduce by 1 dose level

Grade 4 or febrile neutropenia

reduce by 2 dose levels

Diarrhea

Grade 1:    2-3/day > pre-treatment

No change

Grade 2:      4-6/day > pre-treatment

No change

Grade 3:      7-9/day > pre-treatment

reduce by 1 dose level

Grade 4:   ≥10/day > pre-treatment

reduce by 2 dose levels

Other Non-hematologic toxicities (excludes alopecia, anorexia and fatigue).  For mucositis/stomatitis, decrease 5FU only.

Grade 1

No change

Grade 2

Hold until ≤ grade 1, no change in dose

Grade 3

Hold until ≤ grade 2, reduce by 1 dose level

Grade 4

Hold until ≤ grade 2, reduce by 2 dose levels

1 Relative to the starting dose used in the previous cycle. Patients should not be retreated until GI toxicity resolved to baseline (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.



Hepatic Impairment

No dose adjustment required for leucovorin.  OMIT leucovorin if 5FU is omitted.

Transaminases
Bilirubin
Irinotecan
5FU
 
1-1.5 X ULN or Gilbert's
Consider ↓
No change
 > 3 X ULN*
2-4 X ULN
Omit
No change
 
> 4 XULN
Omit
Omit
* or 5 X ULN with liver metastases; consider investigating for reversible causes such as biliary obstruction and reevaluate after stent

 


Renal Impairment

No dose adjustment required for leucovorin.

Creatinine Clearance (mL/min)

Fluorouracil (% previous dose)

Irinotecan (% previous 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

Consider reducing starting dose for patients ≥ 70 years. Monitor patients ≥ 65 years closely.


 
F - Adverse Effects

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

The following adverse effects table is related to FOLFIRI+BEVA:


Very common (≥ 50%)

Common (25-49%)

Less common (10-24%)

Uncommon (< 10%),

but may be severe or life-threatening

  • Myelosuppression ± infection, bleeding (may be severe)
  • Nausea, vomiting
  • Fatigue
  • ECG changes (asymptomatic)
  • Alopecia (generally mild)
  • Abdominal pain
  • Anorexia, weight loss
  • Diarrhea (may be severe)
  • Hypertension
  • Proteinuria
  • Headache
  • ↑ LFTs
  • Constipation
  • Mucositis
  • Cholinergic symptoms
  • Conjunctivitis and / or tearing
  • Rash / dry skin
  • Insomnia
  • Venous thromboembolism
  • Rhinitis
  • Dizziness
  • Musculoskeletal pain
  • Cough, dyspnea
  • Cardiotoxicity
  • Hand-foot syndrome
  • Dyspepsia
  • Flushing
  • Dysphonia
  • Edema
  • Arterial thromboembolism
  • Hypersensitivity
  • Delayed wound healing / dehiscence
  • GI perforation, ulceration, obstruction
  • Fistula, organ perforation
  • Ataxia / acute cerebellar syndrome
  • Bradycardia
  • Confusion
  • Dysarthria
  • Arrhythmia
  • Extrapyramidal or cortical dysfunction
  • Hemolysis
  • Leukoencephalopathy
  • Necrotizing fasciitis
  • Optic neuritis, oculomotor disturbance, tear duct fibrosis
  • Osteonecrosis of jaw and other
  • Pancreatitis
  • Pneumonitis
  • Pulmonary hypertension
  • Radiation recall reaction, photosensitivity
  • Renal failure
  • RPLS / PRES
  • Thrombotic microangiopathy
 
G - Interactions

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


Refer to  bevacizumab drug monograph for additional details on bevacizumab.

 
H - Drug Administration and Special Precautions

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

Different bevacizumab products are not interchangeable.


Refer to  bevacizumab drug monograph for additional details on bevacizumab.

 

 
I - Recommended Clinical Monitoring

Refer to bevacizumab drug monograph for additional details on bevacizumab
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, electrolytes, liver & renal function tests; baseline and before each cycle
  • Clinical toxicity assessment (including diarrhea, infection, dehydration, stomatitis, nausea and vomiting, fatigue and cardiac effects); at each visit
  • Close monitoring of above parameters in elderly patients and patients who are receiving pelvic radiotherapy.
  • 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 regular


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J - Administrative Information

Approximate Patient Visit
FOLFIRI
3 hours
FOLFIRI+BEVA
First cycle: 4.5 hours; Second cycle: 4 hours; Subsequent cycles: 3.5 hours
Pharmacy Workload (average time per visit)
FOLFIRI
37.403 minutes
FOLFIRI+BEVA
43.916 minutes
Nursing Workload (average time per visit)
FOLFIRI
61.667 minutes
FOLFIRI+BEVA
75.333 minutes
 
K - References

Bevacizumab, fluorouracil and irinotecan drug monographs, Cancer Care Ontario.

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.

Clinical Pracitice Guidelines in Oncology (NCCN Guidelines).  Colon Cancer.  Version 3.2015.  NCCN.org

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.

Hurwitz H, Fehrenbacher L, Novotny W et al. Bevacizumab plus irinotecan, fluorouracil and leucovorin in metastatic colorectal cancer. N Engl J Med. 2004; 350: 2335-42.

Mahfoud T, Tanz R, Mesmoudi M, et al. Bevacizumab 5 or 7.5 mg/kg in Metastatic Colorectal Cancer Can Be Infused Safely Over 10 Minutes. J Gastrointest Cancer. 2011 Jan 4. [Epub ahead of print] Reidy DL, Chung KY, Timoney JP, et al. Bevacizumab 5 mg/kg can be infused safely over 10 minutes. J Clin Oncol. 2007;25(19):2691-5.

National Comprehensive Cancer Network. Colon Cancer (Version 2.2017). https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf. Accessed June 30, 2017.

Reidy DL, Chung KY, Timoney JP, et al. Bevacizumab 5 mg/kg can be infused safely over 10 minutes. Journal of Clinical Oncology 2007; 25: 2691-5.

Sobrero A, Ackland S, Clarke S, et al. Phase IV Study of Bevacizumab in Combination with Infusional Fluorouracil, Leucovorin and Irinotecan (FOLFIRI) in First-Line Metastatic Colorectal Cancer. Oncology 2009; 77: 113-9.

Tournigand C, André T, Achile E, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 2004; 22(2): 229-37.

Van Cutsem E, Rivera F, Berry S, et al. Safety and efficacy of first-line bevacizumab with FOLFOX, XELOX, FOLFIRI and fluoropyrimidines in metastatic colorectal cancer: the BEAT study. Ann Oncol 2009; 20: 1842-7.

Zaanan A, Costes L, Gaauthier M et al.  Chemotherapy of advanced small-bowel adenocarcinoma: a multicentre AGEO study. Ann Oncol 2010; 21: 1786-93.


August 2019 added bevacizumab (biosimilar) NDFP form and non-interchangeability description for bevacizumab


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L - Other Notes
Diarrhea can be severe, with either immediate or delayed onset. Patients must be instructed in the use of Loperamide as treatment for diarrhea, and must have a supply of this drug upon starting Irinotecan treatments.
 
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.