Cancer Care Ontario | Cancer Care Ontario (2024)

Regimen Monograph

A - Regimen Name

MFOLFOX6 Regimen

Folinic Acid (Leucovorin)-Fluorouracil-Oxaliplatin

Disease Site

Gastrointestinal

Colorectal
Small bowel and appendix

Intent

Adjuvant
Curative

Regimen Category

Evidence-Informed :

Regimen is considered appropriate as part of the standard care of patients; meaningfullyimproves 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

Adjuvant treatment of stage III or high riskstage II colorectal, small bowel or appendicealcancer
In combination with surgery for curative intent for colorectal cancer patients with resectable or potentially resectable metastases

B - Drug Regimen

oxaliplatin	85mg /m²	IVover 2 hours	Day 1
leucovorin	400mg /m²	IVover 2 hours (concurrently with oxaliplatin)	Day 1
fluorouracil	400mg /m²	IVbolus, after leucovorin	Day 1
THEN
fluorouracil	2400mg /m²	IVcontinuous infusion over 46 hours (single dose)	Start on Day 1

C - Cycle Frequency

REPEAT EVERY 14 DAYS

Adjuvant: Maximum 12 cycles unless disease progression or unacceptable toxicity occurs

Resectable or potentially resectable metastases: For up to 12 cycles, given as pre-op, post-op or perioperatively as "pre- and post-op"

D - Premedication and Supportive Measures

Antiemetic Regimen:

Moderate

Febrile Neutropenia Risk:

Moderate

Also refer toCCO Antiemetic Recommendations.

Screen for hepatitis B virus in all cancer patients starting systemic treatment.Refer to thehepatitis B virus screening and managementguideline.

Avoidmucositis prophylaxis with ice chip as cold temperatures can precipitate or exacerbate acute neurological symptoms of oxaliplatin.

Oxaliplatin premedication (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 theDPD Deficiency Guidance for Cliniciansfor 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

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

Neurotoxicity was graded based on the following scales in some adjuvant colorectal cancer trials.

Neurotoxicity Grade	Description
1	No change or none
2	Mild paresthesias, loss of deep tendon reflexes
3	Mild or moderate objective sensory loss, moderate paresthesias
4	Severe objective sensory loss or paresthesias that interfere with function

Dose Modifications:

Toxicity Grade	Oxaliplatin^	Fluorouracil^
Persistent⁽¹⁾ Grade 2 Neurotoxicity	↓ to 75 mg/m²	No change
Transient⁽¹⁾ Grade 3 Neurotoxicity	↓ to75 mg/m²	No change
Persistent^⁽¹⁾Grade 3 Neurotoxicity or any Grade 4 Neurotoxicity	Discontinue	No change
≥ Grade 3 GI toxicity (after prophylaxis) OR ≥ Grade 3 Platelets OR ≥ Grade 3 Neutropenia (including febrile neutropenia)	↓ to75 mg/m²	Reduce by 20%
Sepsis / septic shock	Discontinue	Discontinue
Other ≥ grade 3 related organ toxicity⁽²⁾	Consider ↓ to 75 mg/m²	Reduce by 20%
Pharyngolaryngeal dysesthesia	Hold; then increase duration of infusion to 6 hours⁽³⁾	No change
Pneumonitis	Hold, investigate; discontinue permanently if confirmed.
Anaphylactic-like reaction	Discontinue permanently
PRES/RPLS
Hemolytic uremic syndrome or any signs of microangiopathic hemolytic anemia
Disseminated intravascular coagulation (DIC)
QT prolongation
Intestinal ischemia or duodenal ulcer
Symptoms of rhabdomyolysis

^Do not re-treat until the ANC ≥ 1.5 x 10⁹/L and the platelets ≥ 75-100 x 10⁹/L, GI and neurotoxicities have resolved and other non-hematologic toxicities ≤ grade 1.
¹ Transient = >7days-<1 cycle; persistent = ≥ 1 cycle
² For skin toxicity, reduce 5FU dose only
³If oxygen saturation is normal, an anxiolytic agent may be given.

Management of Infusion-related reactions:

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

Oxaliplatin:

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

Bilirubin		AST/ALT	oxaliplatin (% previous dose)	fluorouracil (% previous dose)	leucovorin (% previous dose)
1-2 x ULN			No adjustment required	Caution	No change
>2-4 x ULN	And/or	2-4 x ULN	Noadjustment required	Caution	No change
>4 x ULN	And/or	4 x ULN	No data available	OMIT if Bilirubin > 4 x ULN	OMIT if 5FU omitted
ANY	Or	> 4 X ULN	No data available	OMIT if Bilirubin > 4 x ULN	OMIT if 5FU omitted

Renal Impairment

Creatinine Clearance (mL/min)	oxaliplatin (% previous dose)	fluorouracil (% previous dose)	leucovorin (% prevoius dose)
≥50	No adjustment needed	No change	No change
30 to<50	Caution	No change; monitor	No change
<30	Discontinue	Consider dose ↓	No change

Dosage in the Elderly

Patients ≥ 65 years had a higher incidence of GI toxicity, myelosuppression, syncope and fatigue. No dose adjustments were needed but caution should be exercised.

F - Adverse Effects

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

Verycommon (≥ 50%)

Common (25-49%)

Less common (10-24%)

Uncommon (< 10%),

but may be severe or life-threatening

Sensory neuropathy (may be severe, including cranial)
Myelosuppression ± infection, bleeding
Nausea, vomiting
ECG changes (mostly asymptomatic)
↑ LFTs
Diarrhea (may be severe)

Fatigue
Mucositis (may be severe)
Pharyngolaryngeal dysesthesia
Alopecia (mostly mild)

Anorexia, weight changes
Abdominal pain
Constipation
Edema
Hyperglycemia
Musculoskeletal pain
Rash, Hand-foot syndrome
Dysgeusia
Injection site reaction
Abnormal electrolyte(s)
Hypersensitivity

Venous / arterial thromboembolism
QT prolongation, arrhythmia
Cardiotoxicity
Guillain-Barre syndrome
Optic neuritis
Extrapyramidal or cortical dysfunction, acute cerebellar syndrome
RPLS / PRES
Leukoencephalopathy
Nephrotoxicity
Pneumonitis
INR / prothrombin time increased
Disseminated intravascular coagulation
Hemolysis
Hemolytic uremic syndrome
Idiopathic thrombocytopenic purpura
Photosensitivity
Radiation recall reaction
GI obstruction / perforation / ulcer / ischemia
Pancreatitis
Veno-occlusive disease
Rhabdomyolysis
Hearing impaired
Eye disorders

G - Interactions

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

Use of fluorouracil within 4 weeks of treatment with brivudine, sorivudine (and chemically related analogues) is contraindicated.
Thiazide diuretics may decrease renal excretion of fluorouracil; consider an alternative antihypertensive.
Avoid concomitant use of metronidazole and fluorouracil if possible.
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 using oxaliplatin with other nephrotoxic drugs, QT -prolonging drugs or drugs 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, fluorouracil drug monograph(s) for additional details.

Administration

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 notmix with NS, chloride containing or alkaline solutions, or withfluorouracil.
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.
See Also
5-Fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) plus sunitinib or bevacizumab as first-line treatment for metastatic colorectal cancer: a randomized Phase IIb study
Do not mix oxaliplatin with other drugs in the same infusion bag or infusion line.
Infusion may be given at the same time as leucovorin in separate D5W bags using a Y-site, providing trometamol is not used as an excipient. Do not administer concurrently with fluorouracil.
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 (e.g. fluorouracil).
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 250mL D5W if given concurrently with oxaliplatin (over 2 hours) using Y-site administration.
Leucovorin should not be mixed in the same infusion as 5-fluorouracil as a precipitate may form.
Keep refrigerated; protect from light.

Fluorouracil bolus:

Slow push through sidearm of free-flowing IV (5% Dextrose, Normal Saline)
May be mixed in 50mL minibag (NS or D5W); infuse IV over 15 minutes.
Store unopened vials at room temperature (15-25ºC). Protect from light.

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 unopened vials at room temperature (15 to 25ºC). Protect from light.

Refer toSection L - Other Notessectionfor Information on theAntidote for Fluorouracil Overdose.

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

Contraindications:

patients with poor nutritional state
patients with depressed bone marrow function (prior pelvic irradiation / marrow infiltration)
patients with potentially serious infections
patients with known hypersensitivity to the drug, other platinum agents (e.g. cisplatin, carboplatin), or any of their excipients
patients with known complete absence of dihydropyrimidine dehydrogenase (DPD) activity, with fluorouracil.Refer to theDPD Deficiency Guidance for Cliniciansfor more information.
severe renal impairment (CrCl < 30 mL/min), with oxaliplatin
fluorouracil should not be used within 4 weeks of treatment with brivudine, sorivudine or their chemically related analogues.

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.
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 theDPD Deficiency Guidance for Cliniciansfor more information.
Avoid the use of live vaccines.

Pregnancy and Lactation:

This regimen iscontraindicatedfor 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 iscontraindicatedduring 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 thehepatitis B virus screening and managementguideline for monitoring during and after treatment.

Recommended Clinical Monitoring

CBC; baseline and before each cycle
Electrolytes, including magnesium; baseline and before each cycle
Liver function tests; baseline and before each cycle
Renal function tests; baseline and before each cycle
INR, if patient on anticoagulants; baseline and as clinically indicated
Clinical assessment of GI effects, neurotoxicity, infection, bleeding, stomatitis, diarrhea, skin effects, thromboembolism, hypersensitivity, local reactions, respiratory, cardiovascularor ophthalmic 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 regularly

J - Administrative Information

Approximate Patient Visit

3 hours

Pharmacy Workload (average time per visit)

38.381 minutes

Nursing Workload (average time per visit)

69.167 minutes

K - References

Allegra CJ, Yothers G, O’Connell MJ, et al. Initial Safety Report of NSABP C-08: A Randomized Phase III Study of Modified FOLFOX6 With or Without Bevacizumab for the Adjuvant Treatment of Patients With Stage II or III Colon Cancer. J Clin Oncol 2009; 27:3385-90.

André T, Boni C, Mounedji-Boudiaf L, et al. Oxaliplatin, Fluorouracil, and Leucovorin as Adjuvant Treatment for Colon Cancer. N Eng J Med 350:2343-2351, 2004.

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

Mitry E, Fields AL, Bleiberg H, et al. Adjuvant chemotherapy after potentially curative resection of metastases from colorectal cancer: a pooled analysis of two randomized trials. J Clin Oncol 2008;26(30):4906-11.

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

Nordlinger B, Sorbye H, Glimelius B, et al. Peri-operative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet 2008;371(9617):1007-16.

Oxaliplatin, fluorouracil and leucovorin drug monographs, Ontario Health (Cancer Care Ontario).

PEBC Advice Documents or Guidelines

Adjuvant Systemic Chemotherapy for Stage II and III Colon Cancer Following Complete Resection
Preoperative or Postoperative Therapy for the Management of Patients with Stage II or III Rectal Cancer

November 2023 Modified Pregnancy/lactation section

L - Other Notes

Antidote for Fluorouracil Overdose:

Uridine triacetateis 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’sSpecial 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 foruridine triacetatein 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)

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.