Drug Formulary information is intended for use by healthcare professionals. It is not intended to be medical advice. Some of the information, including information about funding for cancer drugs, does not apply to all patients. Cancer treatment plans are unique to each patient. If you are a patient, please speak with your healthcare team to understand how this information applies to you.
FOLFIRI+BEVA; FOLFIRI
Small bowel and appendix
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.
Treatment of metastatic colorectal, small bowel or appendiceal cancer
bevacizumab
New Drug Funding Program
(Bevacizumab (Biosimilar) - Metastatic Colorectal, Small Bowel, or Appendiceal Cancer)
(NDFP Website
)
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
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fluorouracil 2
| 2400 mg /m² | IV continuous infusion over 46 hours only | Start on Day 1 |
|
with or without:
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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.
REPEAT EVERY 14 DAYS
Until evidence of disease progression or unacceptable toxicity
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
Doses should be modified according to the protocol by which the patient is being treated.
Patients should be tested for DPD deficiency before starting treatment with fluorouracil. Refer to the DPD Deficiency Guidance for Clinicians for more information.
In patients with unrecognized DPD deficiency, acute, life-threatening toxicity may occur; if grade 2-4 acute toxicity develops, treatment should be stopped immediately and permanent discontinuation considered based on clinical assessment of the toxicities.
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. 2 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. |
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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
|
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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.
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 |
|
|
|
|
Refer to irinotecan, leucovorin, fluorouracil drug monograph(s) for additional details
Refer to bevacizumab drug monograph for additional details on bevacizumab.
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.
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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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 Practice 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.
- Continuous versus Intermittent Chemotherapy Strategies in Inoperable, Advanced Colorectal Cancer
- Strategies of Sequential Therapies in Unresectable, Metastatic Colorectal Cancer Treated with Palliative Intent
- The Role of Primary Tumour Location in the Selection of Biologics for the Treatment of Unresectable Metastatic Colorectal Cancer
April 2023 Updated DPD deficiency information in the Dose Modifications section and fluorouracil antidote information in the Other Notes section.
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.
Antidote for Fluorouracil Overdose:
Uridine triacetate is a prodrug of uridine and is a specific antidote for treating fluorouracil overdose or severe early onset toxicities. If available, consider administering as soon as possible (i.e. within 96 hours) for suspected overdose. If not available, treatment is symptomatic and supportive.
For usage approval and supply, contact Health Canada’s Special Access Program (SAP) (Phone: 613-941-2108. On-call service is available for emergencies). Uridine triacetate (Vistogard®) is supplied by its manufacturer in the United States (Wellstat Therapeutics).
The recommended dosing and administration for uridine triacetate in patients ≥18 years is:
- 10 grams (1 packet of coated granules) orally every 6 hours for 20 doses in total, without regards to meals.
- Granules should not be chewed. They should be mixed with 3 to 4 ounces of soft foods such as applesauce, pudding or yogurt.
- The dose should be ingested within 30 minutes of preparation, followed by at least 4 ounces of water.
- Refer to the prescribing information on dose preparation for NG-tube or G-tube use.
Additional resources on the management of fluorouracil infusion overdose:
- Management of Fluorouracil Infusion Overdose Guideline (Alberta Health Services)
- Management of Fluorouracil Infusion Overdose at the BCCA - Interim Guidance (BC Cancer Agency)
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.
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