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A - Regimen Name

MFOLFIRINOX Regimen
Folinic Acid (Leucovorin)-Fluorouracil-Irinotecan-Oxaliplatin


Disease Site
Gastrointestinal
Pancreas


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

Treatment of locally advanced unresectable or metastatic pancreatic adenocarcinoma in patients with good performance status

 
B - Drug Regimen

oxaliplatin
85 mg /m² IV over 2 hours Day 1


THEN,

leucovorin
400 mg /m² IV over 2 hours Day 1


30 minutes after starting leucovorin, give:

irinotecan
150 mg /m² IV over 90 minutes, concurrently with leucovorin Day 1


Then,
 

fluorouracil
2400 mg /m² IV continuous infusion over 46 hours (single dose) Start on Day 1
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C - Cycle Frequency

REPEAT EVERY 14 DAYS

Continue until disease progression or unacceptable toxicity; in the clinical trial 12 cycles were recommended for responding patients, while the median number of cycles was 10 (range 1-47).

 
D - Premedication and Supportive Measures

Antiemetic Regimen:

Moderate

Other Supportive Care:

  • Screen for hepatitis B virus in all cancer patients starting systemic treatment. Refer to the hepatitis B virus screening and management guideline.
  • For irinotecan cholinergic adverse effects (early diarrhea):
    • Unless contraindicated, atropine 0.25-1mg IV/SC may be given
    • Prophylactic atropine may be considered in patients who have experienced cholinergic symptoms
  • Loperamide must be provided.  Diarrhea (including abdominal cramps) may be severe and delayed with irinotecan.
  • Give loperamide 4mg at the onset of diarrhea, then 2mg q2h until patient is diarrhea-free for 12 hours. During the night the patient may take 4mg of loperamide every 4 hours.
  • May consider GCSF as secondary prophylaxis for neutropenia (Conroy et al, 2011).
  • May consider antibiotics for patients with ileus, fever or febrile neutropenia.
  • Avoid mucositis prophylaxis with ice chips as cold temperatures can precipitate or exacerbate acute neurological symptoms of oxaliplatin.


Premedication for oxaliplatin (prophylaxis for infusion reactions):

  • There is insufficient evidence that routine prophylaxis with pre-medications reduces IR rates.
  • Consider corticosteroids and H1-receptor antagonists ± H2-receptor antagonists in high-risk patients (i.e. ≥ cycle 6, younger age, female gender, prior platinum exposure, platinum-free interval ≥ 3 years).
 
E - Dose Modifications

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 acute grade 2-4 toxicity develops, treatment should be stopped immediately and permanent discontinuation considered based on clinical assessment of the toxicities.

 

 

Dosage with toxicity

Do not start new cycle until platelets ≥ 100 x 109/L and ANC ≥ 1.5 x 109/L, recovery from diarrhea (to baseline without loperamide for at least 24 hours), and other non-hematologic toxicities have recovered to ≤grade 2.

Doses should be adjusted based on the worst preceding toxicity. Do not re-escalate dose if reduced for toxicity. 

 

No dose adjustment is required for leucovorin. Leucovorin should be omitted if fluorouracil is omitted.

Dose Levels:

 

Drug Dose level 0
(mg/m2)
Dose level -1*
(mg/m2)
Irinotecan 150 120
Oxaliplatin 85 60
Fluorouracil infusion 2400 1800

* If further dose reduction is required, consider a 20% dose reduction or discontinuing the regimen.

 

 

 

Dose Modifications:

 

 
Toxicity
Occurrence
Irinotecan dosea,b
Oxaliplatin dosea,b
Fluorouracil dosea,b
Febrile neutropenia OR
Grade 4 ANC > 7 d OR
Delay 1-2 weeks for ≥ Grade 2 ANC
1st
↓ 1 dose level
No change
 
2nd
Maintain same dose level
↓ 1 dose level
3rd Discontinue

≥ grade 3 platelets OR

Delay 1-2 weeks for platelets <100 x 109/L

1st
No change
↓ 1 dose level
no change
2nd
 
↓ 1 dose level
Maintain same dose level
3rd

Discontinue

 

Diarrhea ≥ grade 3 OR

Diarrhea with fever or ≥ Grade 3 ANC

1st
↓ 1 dose level
No change
No change
2nd
Maintain same dose level
↓ 1 dose level
↓ 1 dose level
3rd Discontinue
Grade 3 or 4 mucositis or hand-foot syndrome - No change No change ↓ 1 dose level

Grade 2 persistent neurotoxicity

-
No change
↓ 1 dose level
No change
Grade 3 neurotoxicity (recovers prior to next cycle) - No change  ↓ 1 dose level No change
Grade 3 persistent neurotoxicity
OR
Grade 4 neurotoxicity
Any No change Discontinue No change

Grade 2 other non-hematological

-
Consider ↓
Consider ↓
Consider ↓

Grade 3 other non-hematological

-
↓ 1 dose level
↓ 1 dose level
↓ 1 dose level
Pneumonitis Any Discontinue Discontinue Discontinue

Grade 4 other non-hematological 

OR

RPLS

OR

Hemolytic uremic syndrome or any signs of microangiopathic hemolytic anemia

Any Discontinue Discontinue Discontinue

Pharyngolaryngeal dysesthesia

 Any
 -
↑ infusion to 6 hours
-
aDo not treat until ANC ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L, diarrhea resolved to baseline and other toxicity ≤ grade 2.  Do not re-escalate dose if reduced for toxicity. 
bConsider discontinuing if cycle delayed for > 2 weeks.

 

 

Management of Oxaliplatin Infusion-Related Reactions:

Also refer to the CCO guideline for detailed description of Management of Cancer Medication-Related Infusion Reactions.

 

Grade Management Re-challenge
1 or 2
  • Stop or slow the infusion rate.
  • Manage the symptoms.
     

Restart:

  • After symptom resolution, restart with pre-medications ± reduced infusion rate.
  • Consider pre-medications* and infusing at a reduced infusion rate prior to re-challenge.
     
  • May consider adding oral montelukast ± oral acetylsalicylic acid.
3 or 4
  • Stop treatment.
  • Aggressively manage symptoms.
  • Re-challenge is discouraged, especially if vital signs have been affected.
     
  • Consider desensitization if therapy is necessary.

*Up to 50% of patients can experience recurrent reactions during re-challenge despite using pre-medications (e.g. corticosteroid and H1/H2-receptor antagonist).

 



Hepatic Impairment

Transaminases
 
Bilirubin^
Irinotecan dose
Oxaliplatin dose
5FU dose
 
 
1 to 1.5 x ULN or Gilbert's
Consider ↓
No change
No change
 > 3 to 5 X ULN*
and/or
>1.5 to 4 X ULN
Omit
No change
Consider ↓ (e.g. 75% of previous dose)
>5 to 10 X ULN and/or >1.5 to 4 X ULN Omit No change Consider ↓ (e.g. 50-75% of previous dose)
> 10 X ULN
and/or
> 4 X ULN
Omit
No info found
Omit
* or >5 X ULN with liver metastases

^ If bilirubin ↑, consider investigating for reversible causes such as biliary obstruction and re-evaluate after stent.


Renal Impairment

Creatinine Clearance (mL/min)

oxaliplatin

(% previous dose)

fluorouracil

(% previous dose)

irinotecan

(% previous dose)

≥50
No change
No change
No change

30 to <50            

Caution
No change
No change
<30
Discontinue
Consider dose reduction
Caution

 
F - Adverse Effects

Refer to oxaliplatin, leucovorin, irinotecan, 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

  • Sensory neuropathy
  • Myelosuppression ± infection, bleeding (may be severe)
  • Nausea/ vomiting
  • Fatigue
  • Alopecia
  • ↑ Bilirubin/ LFTs
  • Diarrhea (early 51%; late 88%; may be severe)
  • Anorexia, weight loss

 

  • Mucositis
  • Pharyngolaryngeal dysesthesia
  • Constipation
  • Cholinergic symptoms
  • Conjunctivitis/tearing
  • Cough/ dyspnea
  • Rash/dry skin/ photosensitivity
  • Anorexia
  • Insomnia
  • Headache
  • Dizziness
  • Edema
  • Rhinitis
  • Musculoskeletal pain
  • Hyperglycemia
  • Hand-foot syndrome
  • Flushing
  • Dyspepsia
  • Dysgeusia
  • Abnormal electrolytes (↓Ca, K, Na)
  • Injection site reaction
  • Hypersensitivity
  • Cardiotoxicity
  • Arrhythmia/QT prolongation
  • Arterial/venous thromboembolism
  • DIC
  • ITP
  • Hypotension
  • Radiation recall reaction
  • GI ulceration/ ischemia/ obstruction/ perforation
  • Hemolysis
  • Hemolytic uremic syndrome
  • Hepatic necrosis
  • VOD
  • Pancreatitis
  • Acute cerebellar syndrome
  • Rhabdomyolysis
  • Guillain-Barre syndrome
  • Extrapyramidal disorder
  • Leukoencephalopathy
  • RPLS/PRES
  • Optic neuritis
  • Seizure
  • Renal failure
  • Pneumonitis
  • Hearing impairment
 
G - Interactions

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


  • Use of fluorouracil within 4 weeks of treatment with brivudine, sorivudine (and chemically related analogues) is contraindicated.

  • Azole antifungals are contraindicated with irinotecan (discontinue one week before the first dose of irinotecan).

  • Avoid concomitant use of metronidazole and fluorouracil if possible.

  • Avoid concomitant use of strong CYP3A4 inhibitors and inducers with irinotecan.

  • Avoid concomitant use of prochlorperazine (on same day of irinotecan treatment), turmeric and azatanavir with irinotecan.

  • Thiazide diuretics may decrease renal excretion of fluorouracil; consider an alternative antihypertensive.

  • Monitor INR closely while on concomitant warfarin and fluorouracil or oxaliplatin; adjust warfarin dose accordingly.

  • Monitor phenytoin levels if used concurrently with fluorouracil.

  • Monitor for toxicity when oxaliplatin is used with other drugs that are nephrotoxic, prolong QT or are associated with rhabdomyolysis.

  • Caution with the concurrent use of cimetidine due to interference with fluorouracil metabolism; fatal cases have been reported.

 
H - Drug Administration and Special Precautions

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


Oxaliplatin:

  • Oxaliplatin is administered by intravenous infusion.

  • Oxaliplatin should always be administered before fluorouracil.

  • May be mixed in 250-500 mL bag of D5W only.  Do not mix oxaliplatin with NS, chloride containing or alkaline solutions, or with fluorouracil.

  • Administer by slow infusion. Concentration must be between 0.2 to 0.7 mg/mL

  • Infuse IV over 2 hours. Increasing infusion time to 6 hours may decrease acute toxicity such as pharyngolaryngeal dysesthesia.

  • Do not mix oxaliplatin with other drugs in the same infusion bag or infusion line.

  • If another drug is given before oxaliplatin, flush infusion line with D5W before giving oxaliplatin. Flush the line with D5W after oxaliplatin before giving a subsequent drug.

  • The compatibility of oxaliplatin solution for infusion has been tested with representative, PVC-based, administration sets.

  • Do not use with injection equipment containing aluminum, as this can degrade platinum compounds.

  • Unopened vials should be stored at 15-30°C; protect from light.


Leucovorin:

  • Leucovorin may be diluted in 250 mL D5W.
  • Leucovorin should not be mixed in the same infusion as 5-fluorouracil as a precipitate may form.

  • Keep refrigerated; protect from light.

 


Irinotecan:

  • Mix in 500mL bag D5W in a concentration range between 0.12 to 3 mg/mL; infuse IV over 90 minutes

  • Infusion may be given at the same time as leucovorin in separate D5W bags using a Y-site.

  • 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.


 

Fluorouracil:

  • IV CONTINUOUS INFUSION:

    • Refer to local guidelines on preparation of fluorouracil IV infusion.

    • Continuous infusion via central line or PICC using CADD infusion pump, infusor bottle or similar device

    • Incompatible with doxorubicin, epirubicin, diazepam, methotrexate and cytarabine; line must be flushed between administrations of fluorouracil and these agents.

    • Store at room temperature (15 to 25ºC). Protect from light.


Refer to Section L - Other Notes section for Information on the Antidote for Fluorouracil Overdose.


Contraindications:

  • Hypersensitivity to the fluorouracil, irinotecan, leucovorin, oxaliplatin or to other platinum agents (e.g. cisplatin, carboplatin) or to any component of the formulation.

  • Patients with severe renal impairment (CrCl < 30 mL/min), with oxaliplatin

  • Patients with poor nutritional state

  • Patients with depressed bone marrow function (prior pelvic irradiation / marrow infiltration)

  • Patients with potentially serious infections

  • Patients with known complete absence of dihydropyrimidine dehydrogenase (DPD) activity, with fluorouracil. Refer to the DPD Deficiency Guidance for Clinicians for more information.

  • Avoid in patients with hereditary fructose intolerance since the irinotecan formulation contains sorbitol.

  • Avoid the use of live or live attenuated vaccines.

  • Fluorouracil should not be used within 4 weeks of treatment with brivudine, sorivudine or their chemically related analogues. (See interactions section)

  • Irinotecan should not be co-administered with azole antifungals (ketoconazole etc. See Interactions section)


Warnings/Precautions:

  • Oxaliplatin may result in dizziness or visual disturbances (including transient vision loss) in some patients; patients should exercise caution in driving or operating machinery.

  • Do not give oxaliplatin intraperitoneally.

  • Irinotecan is not recommended for use in patients with ECOG performance status 3 or 4, or in patients with moderate or severe increases in bilirubin.

  • Carefully monitor and consider irinotecan dose reduction for elderly patients, patients with poor performance status (= 2), limited marrow reserve, 3rd space accumulation, Gilbert’s syndrome and patients with reduced UGT1A1 activity; they may be more susceptible to the toxic effects of irinotecan.

  • Concurrent administration of irinotecan with irradiation is not recommended. Patients with prior pelvic or abdominal irradiation are at an increased risk of severe myelosuppression following irinotecan therapy.

  • Use fluorouracil with extreme caution in patients who:

    • have undergone recent major surgery,

    • have renal or hepatic impairment,

    • have widespread bone marrow involvement,

    • have previous use of other myelosuppressive chemotherapeutic agents,

    • have a history of high dose irradiation to bone marrow-bearing areas,

    • have a history of heart disease,

    • or are suspected to have DPD deficiency. Refer to the DPD Deficiency Guidance for Clinicians for more information.

 


Pregnancy/Lactation:

  • This regimen is contraindicated for use in pregnancy. Adequate contraception should be used by patients and their partners while on treatment and after the last treatment dose. Recommended methods and duration of contraception may differ depending on the treatment. Refer to the drug monograph(s) for more information.

  • Breastfeeding is contraindicated during this treatment and after the last treatment dose. Refer to the drug monograph(s) for recommendations after the last treatment dose (if available).

  • Fertility effects:  Yes

 
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.

Refer to the hepatitis B virus screening and management guideline for monitoring during and after treatment.

Recommended Clinical Monitoring

  • CBC; baseline and before each cycle
  • Liver and renal function tests; baseline and before each cycle
  • Electrolytes, including magnesium; baseline and before each cycle
  • INR for patients on warfarin; baseline and as clinically indicated
  • Routine toxicity rating of diarrhea and other GI effects, fatigue, cholinergic symptoms, hypersensitivity, pneumonitis, bleeding, infection, dehydration, pancreatitis, neuropathy, thromboembolism, local reactions, skin (including rash, hand-foot syndrome), ophthalmic and cardiac toxicity.
  • 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 regularly

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J - Administrative Information

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

Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011;364:1817-25.

Conroy T, Hammel P, Hebbar M, et al. FOLFIRINOX or gemcitabine as adjuvant therapy for pancreatic cancer. N Engl J Med 2018;379:2395-406.


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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.