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MFOLFOX6+BEVA; MFOLFOX6

Cancer Type: Gastrointestinal, Colorectal, Small bowel and appendix  Intent: Palliative
Regimen Category: Evidence-Informed
Funding:
New Drug Funding Program
    Oxaliplatin - Second Line - Metastatic Colorectal Small Bowel or Appendiceal Cancer
New Drug Funding Program
    Oxaliplatin - First 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

MFOLFOX6 Regimen
Folinic Acid (Leucovorin)-Fluorouracil-Oxaliplatin
MFOLFOX6+BEVA Regimen
Folinic Acid (Leucovorin)-Fluorouracil-Oxaliplatin-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

mFOLFOX6:  First-line and second-line treatment of metastatic colorectal, small bowel or appendiceal cancer
mFOLFOX6+BEVA:  First-line treatment of metastatic colorectal, small bowel or appendiceal cancer


Supplementary Public Funding

oxaliplatin
New Drug Funding Program (Oxaliplatin - Second Line - Metastatic Colorectal Small Bowel or Appendiceal Cancer) (NDFP Website)

oxaliplatin
New Drug Funding Program (Oxaliplatin - First Line - Metastatic Colorectal Small Bowel or Appendiceal Cancer) (NDFP Website)

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.
 

oxaliplatin
85 mg /m² IV in 500mL D5W over 120 minutes Day 1
leucovorin
400 mg /m² IV diluted in D5W over 120 minutes (concurrently with oxaliplatin) Day 1
fluorouracil
400 mg /m² IV bolus, after leucovorin Day 1
THEN
fluorouracil
2400 mg /m² IV continuous infusion over 46 hours only Start on Day 1
with or without:
bevacizumab

1, 2

5 mg /kg IV over 90 minutes for initial dose Day 1

1If 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.

2Sequence of administration:  Bevacizumab has been given prior to chemotherapy in several phase III trials.

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C - Cycle Frequency

REPEAT EVERY 14 DAYS

Until disease progression or unacceptable toxicity

 
D - Premedication and Supportive Measures

Antiemetic Regimen:

Moderate

Other Supportive Care:

Also refer to CCO Antiemetic Summary

 
E - Dose Modifications

Doses should be modified according to the protocol by which the patient is being treated. The following recommendations are in use at some centres.

Refer to bevacizumab drug monograph for details on bevacizumab.

Dosage with toxicity

See general recommendations for hematologic toxicity.

mFOLFOX:    No dose adjustments required for leucovorin.

 

Neurotoxicity was graded based on the following scales in some metastatic colorectal cancer trials. 
Neurotoxicity Grade
Description
1
Resolved and did not interfere with functioning
2
Interfered with function but not daily activities
3
Pain or functional impairment that interfered with daily activities
4
Persistent impairment that is disabling or life-threatening
 
 
Toxicity Grade
Oxaliplatin^
Fluorouracil^
Persistent(1) Grade 2  neurotoxicity
↓ from 85 → 65 mg/m2
No change
Transient(1) Grade 3 neurotoxicity
↓ from 85 → 65 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 or 4 Platelets OR
Grade 3 or 4 Neutropenia (including febrile neutropenia)*
↓ from 85 → 65 mg/m2 *
Reduce by 20% *
Sepsis / septic shock Discontinue Discontinue
Other ≥ grade 3 related organ toxicity(2)
↓ from 85 → 65 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.
RPLS or Hemolytic uremic syndrome or any signs of microangiopathic hemolytic anemia
Discontinue permanently

^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.

* Discontinue if sepsis / septic shock

 

 

 

 



Hepatic Impairment

Bilirubin
 
AST/ALT
oxaliplatin
(% previous dose)

fluorouracil (% previous dose)

leucovorin (% previous dose)

1-2 x ULN

 
 

No change

Caution
No change

>2-4 x ULN

 And/or

2-4 x ULN

No change

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 (% previous dose)
50-80

No change

No change

No change
30-<50                         
Caution

No change

No change
<30
Discontinue

Caution, consider dose ↓

No change

 
F - Adverse Effects

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

The following adverse effects table is related to mFOLFOX6.  ​​​​Refer to bevacizumab drug monograph for details on bevacizumab:


Very common (≥ 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.


Refer to bevacizumab drug monograph for details on bevacizumab.

 
H - Drug Administration and Special Precautions

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

Different bevacizumab products are not interchangeable.


Refer to bevacizumab drug monograph for details on bevacizumab.

 
I - Recommended Clinical Monitoring

Refer to bevacizumab drug monograph for 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; baseline and before each cycle

  • Electrolytes, including magnesium; baseline and regular

  • INR, if patient on anticoagulants; baseline and regular

  • Liver function tests; baseline and regular

  • Renal function tests; baseline and regular

  • Clinical assessment of GI effects, neurotoxicity, infection, bleeding, stomatitis, diarrhea, skin effects, thromboembolism, hypersensitivity, local reactions, respiratory or ophthalmic effects; at each visit

  • Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version


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J - Administrative Information

Approximate Patient Visit
MFOLFOX6
3 hours
MFOLFOX6+BEVA
3.5 to 4 hours
Pharmacy Workload (average time per visit)
MFOLFOX6
38.381 minutes
MFOLFOX6+BEVA
44.894 minutes
Nursing Workload (average time per visit)
MFOLFOX6
69.167 minutes
MFOLFOX6+BEVA
74.167 minutes
 
K - References

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 Pracitice 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.

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]

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

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

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.

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.

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 Removed archived PEBC guideline link, updated Adverse Effects section, added bevacizumab (biosimilar) NDFP form and non-interchangeability description for bevacizumab


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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.
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