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MFOLFOX6

Cancer Type: Gastrointestinal, Colorectal, Small bowel and appendix  Intent: Adjuvant
Regimen Category: Evidence-Informed
Funding:
New Drug Funding Program
    Oxaliplatin - Adjuvant Colorectal Small Bowel or Appendiceal Cancer
New Drug Funding Program
    Oxaliplatin - With Surgery for Curative Intent for CRC SBAC Pts with Resectable or Potentially Resectable Liver Mets
Evidence Building Program
    Oxaliplatin (EBP) - Colorectal Cancer Patients with Resectable or Potentially Resectable Extrahepatic Metastases
Evidence Building Program
    Oxaliplatin (EBP) - Supplemental 1
Evidence Building Program
    Oxaliplatin (EBP) - Supplemental 2
A - Regimen Name

MFOLFOX6 Regimen
Folinic Acid (Leucovorin)-Fluorouracil-Oxaliplatin


Disease Site
Gastrointestinal - Colorectal
Gastrointestinal - Small bowel and appendix

Intent
Adjuvant

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
  • Adjuvant treatment of stage III or high risk stage II colorectal, small bowel or appendiceal cancer 
  • Perioperative chemotherapy for metastatic colorectal, small bowel and appendiceal cancer patients deemed by a standards compliant Multidisciplinary Cancer Conference (MCC) or equivalent, to have the following metastases that are resectable or potentially resectable:
    • Liver metastases1, OR
    • Lung metastases2, OR
    • Liver and lung metastases2 ; OR
    • Liver and non-pulmonary extrahepatic metastases2
 

Supplementary Public Funding

oxaliplatin
New Drug Funding Program (Oxaliplatin - Adjuvant Colorectal Small Bowel or Appendiceal Cancer)

oxaliplatin
New Drug Funding Program (Oxaliplatin - With Surgery for Curative Intent for CRC SBAC Pts with Resectable or Potentially Resectable Liver Mets) (1 )

oxaliplatin
Evidence Building Program (Oxaliplatin (EBP) - Colorectal Cancer Patients with Resectable or Potentially Resectable Extrahepatic Metastases) (excludes small bowel or appendiceal cancer )

oxaliplatin
Evidence Building Program (Oxaliplatin (EBP) - Supplemental 1) (excludes small bowel or appendiceal cancer )

oxaliplatin
Evidence Building Program (Oxaliplatin (EBP) - Supplemental 2) (excludes small bowel or appendiceal cancer )

 
B - Drug Regimen

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 (single dose) Start on Day 1
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C - Cycle Frequency

REPEAT EVERY 14 DAYS

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

Resectable or potentially resectable metastases: A randomized controlled trial has used 6 cycles before surgery and 6 cycles post-surgery (funded by NDFP for up to 12 cycles, given as pre-op, post-op or perioperatively as “pre- and post-op”).  Patients who progress on FOLFOX may be transitioned over to other appropriate first-line metastatic regimens (Refer to January 8, 2013 funding announcement).

 

 

 
D - Premedication and Supportive Measures

Antiemetic Regimen:

Moderate


Febrile Neutropenia Risk:

Low

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 have been adapted from clinical trials or product monographs and could be considered.

Dosage with toxicity

See appendix 6 for general recommendations for hematologic toxicity.
No dose adjustments required for leucovorin.

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 Modfications:

Toxicity Grade

Oxaliplatin^

Fluorouracil^

Persistent(1) Grade 2  Neurotoxicity

↓ from 85 → 75 mg/m2
No change

Transient(1) Grade 3 Neurotoxicity

↓ from 85 → 75 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 → 75 mg/m2 *

 

Reduce by 20% *
Sepsis / septic shock Discontinue Discontinue
Other ≥ grade 3 related organ toxicity(2)
↓ from 85 → 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.

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 = >7days-<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
(% prevoius dose)
leucovorin
(% prevoius dose)
50 - 80
No change
No change No change
30 - <50                         
Caution
No change; monitor No change
<30
Discontinue
Consider dose ↓ No change

 
F - Adverse Effects

Refer to oxaliplatin, leucovorin, 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 (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.

 
H - Drug Administration and Special Precautions

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


 

 

 
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.

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
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 Pracitice 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, Cancer Care Ontario.


August 2019 removed archived PEBC guideline link


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L - Other Notes

Perioperative Chemotherapy in Liver Metastases:

The randomized controlled trial by Nordlinger et al showed a non-significant 7.3% improvement in PFS in all randomized patients at three years in the surgery plus chemotherapy group versus surgery alone.  Re-analysis of the subset of patients who were eligible to enter the trial or received resection indicated a significant increase in PFS.  Reversible postoperative complications occurred significantly more often after chemotherapy than with surgery alone.  Perioperative chemotherapy reduced the relative risk of relapse by one quarter.

A pooled analysis of two smaller studies of 5FU postoperative chemotherapy showed trends in PFS and overall survival favouring the surgery plus chemotherapy group that did not reach statistical significance.

 
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.