MFOLFOX6+BEVA

REPEAT EVERY 14 DAYS

Until disease progression or unacceptable toxicity

Also refer to CCO Antiemetic Recommendations.

Screen for hepatitis B virus in all cancer patients starting systemic treatment. Refer to the hepatitis B virus screening and management guideline.

Avoid mucositis 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).

Bevacizumab premedication (prophylaxis for infusion reactions):

• Routine primary prophylaxis is not recommended; the use of secondary prophylaxis pre-medications should be based on clinical judgement.

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

Bevacizumab should not be initiated in patients with recurrent hemoptysis, uncontrolled hypertension or wounds that require healing.

Prior to treatment, a dental evaluation should be performed and major dental procedures completed.

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.

mFOLFOX:

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

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

_{^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 = >7 days - <1 cycle;  persistent = ≥ 1 cycle}
² _{For skin toxicity, reduce 5FU dose only}
³ _{If oxygen saturation is normal, an anxiolytic agent may be given.}

Bevacizumab:

Dose reductions are not recommended. Bevacizumab should be held or discontinued based on toxicity.

Management of Infusion-related reactions:

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

Oxaliplatin:

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

Bevacizumab:

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

Use bevacizumab with caution; patients > 65 years old have an increased risk of arterial thrombotic events as well as myelosuppression, fatigue, proteinuria, hypertension, dizziness, dysphonia, anorexia and GI effects (except gastrointestinal perforation).

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

Refer to oxaliplatin, leucovorin, fluorouracil, bevacizumab 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.

• Do not use with diuretics in patients who are receiving bevacizumab and platinum-based chemotherapy (oxaliplatin).

• 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.

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

Administration

Bevacizumab:

Different bevacizumab products are not interchangeable.

• Do not administer as an IV push or bolus.

• Bevacizumab infusions should not be administered or mixed with dextrose or glucose solutions due to potential for drug degradation.

• Mix in 100 mL bag NS. (Dilution should be 1.4 -16.5 mg/mL). 

• Compatible with PVC or polyolefin bags.

• Do not shake.  Should not be mixed or diluted with other drugs.

• Infused over 90 minutes as loading dose, if well tolerated next infusion can be given over 60 minutes; if well tolerated, can thereafter be given over 30 minutes as maintenance dose

• Bevacizumab rapid infusion (over 10 minutes) has safely been administered with no significant increase in infusion reactions (for 5mg/kg and 7.5mg/kg doses).

• Refrigerate unopened vials and protect from light; do not freeze.

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 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.

• 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 to Section L - Other Notes section for Information on the Antidote 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 untreated CNS metastases

• patients with known hypersensitivity to the drugs, other platinum agents (e.g. cisplatin, carboplatin), or any of their excipients

• patients with known hypersensitivity to Chinese hamster ovary cell product or to other recombinant human or humanized antibodies

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

• Avoid the use of live vaccines.

• 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 the DPD Deficiency Guidance for Clinicians for more information.

• Bevacizumab should not be initiated for at least 28 days following major surgery or until wound healing has occurred; hold for 28 days prior to major elective surgery

• The safety and efficacy of concurrent radiotherapy and bevacizumab has not been established

• Use bevacizumab with caution in:

  • Elderly patients

  • Patients with a history of arterial thromboembolism or significant cardiovascular disease or cardiac failure

  • Patients with coagulopathies (congenital, acquired or therapeutic)

  • Patients with recurrent hemoptysis (>2.5ml), serious hemorrhage, or with squamous NSCLC

  • Patients with colorectal cancer and colorectal stents - increased risk of GI perforation has been reported

  • Patients given concurrent bisphosphonates or other anti-angiogenic agents, given increased risk of ONJ

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

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

Suggested Clinical Monitoring

Braun MS, Adab F, Bradley C, et al. Modified de Gramont with oxaliplatin in the first-line treatment of advanced colorectal cancer. British Journal of Cancer 2003; 89: 1155 – 8.

Cassidy J, Clarke S, Dı´az-Rubio E, et al. XELOX vs FOLFOX-4 as first-line therapy for metastatic colorectal cancer: NO16966 updated results. Br J Cancer 2011; 105: 58–64.

Cheeseman SL, Joel SP, Chester JD, et al. A ‘modified de Gramont’ regimen of fluorouracil, alone and with oxaliplatin, for advanced colorectal cancer. British Journal of Cancer 2002: 87; 393 – 9.

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

Hochster HS, Hart LL, Ramanathan RK, et al. Safety and Efficacy of Oxaliplatin and Fluoropyrimidine Regimens With or Without Bevacizumab As First-Line Treatment of Metastatic Colorectal Cancer: Results of the TREE Study. J Clin Oncol 2009; 26: 3523-9.

Oxaliplatin, fluorouracil and leucovorin drug monographs, Cancer Care Ontario.

Ryan DP, Clark JW, Kulke MH, et al. A Phase II study of modified deGramont 5-Fluorouracil, leucovorin, and oxaliplatin in previously treated patients with metastatic colorectal cancer. Cancer Investigation 2003; 21(4): 505-11.

Saltz LB, Clarke S, Dı´az-Rubio, et al. Bevacizumab in Combination With Oxaliplatin-Based Chemotherapy As First-Line Therapy in Metastatic Colorectal Cancer: A Randomized Phase III Study. J Clin Oncol 2008; 26:2013-9.

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.

• Strategies of Sequential Therapies in Unresectable, Metastatic Colorectal Cancer Treated with Palliative Intent
• Continuous versus Intermittent Chemotherapy Strategies in Inoperable, Advanced Colorectal Cancer
• The Role of Primary Tumour Location in the Selection of Biologics for the Treatment of Unresectable Metastatic Colorectal Cancer