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FLOX

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
A - Regimen Name

FLOX Regimen
Fluorouracil-Leucovorin-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 and high risk stage II colorectal cancer


Supplementary Public Funding

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

 
B - Drug Regimen

oxaliplatin
1
85 mg /m² IV in 500mL D5W over 120 minutes Days 1, 15 and 29

 

 

leucovorin
1
500 mg /m² IV diluted in D5W over 120 minutes (after oxaliplatin infusion on days 1, 15, and 29) Days 1, 8, 15, 22, 29 and 36
fluorouracil
500 mg /m² IV as bolus, 1 hour after leucovorin infusion has begun Days 1, 8, 15, 22, 29, 36

Oxaliplatin and leucovorin were not given concurrently in the trial.

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C - Cycle Frequency

REPEAT EVERY 56 DAYS
For a maximum total of 3 cycles unless disease progression or unacceptable toxicity occurs

 
D - Premedication and Supportive Measures

Antiemetic Regimen:

Moderate (D1, 15, 29)
Low (D8, 22, 36)


Febrile Neutropenia Risk:

Moderate

Other Supportive Care:

Also refer to CCO Antiemetic Recommendations.

 
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

Adjuvant
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

↓ 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 Discontinue4
Other ≥ grade 3 related organ toxicity(2)
↓ from 85 → 75 mg/m2
Reduce by 20%
 
Toxicity Grade Oxaliplatin^ Fluorouracil^
Pharyngolaryngeal dysesthesia
 

Hold; then increase duration of infusion to 6 hours(3)

No change

 

Pneumonitis

Hold, investigate; discontinue permanently if confirmed4

PRES or hemolytic uremic anemia or any signs of microangiopathic hemolytic anemia
Discontinue permanently4

^Do not re-treat until the ANC ≥ 1.5 x 109/L and the platelets ≥ 100 x 109/L, GI and neurotoxicities have resolved and other non-hematologic toxicities ≤ grade 1.
1 Transient = 7-14 days;  persistent = ≥ 14 days
2 For skin toxicity, reduce 5FU dose only
3 If oxygen saturation is normal, an anxiolytic agent may be given.
4 Do not give leucovorin if fluorouracil is omitted.
* Discontinue if 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

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.  Efficacy in the adjuvant setting was not confirmed.

Dosage based on gender:

Women may be at higher risk of severe (grades 3-4) neutropenia in adjuvant treatment of colorectal cancer.

 


 
F - Adverse Effects

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


Most Common Side Effects 

Less Common Side Effects, but may be
Severe or Life-Threatening

  • Neuropathy (may be severe)
  • Nausea, vomiting
  • ↑ LFTs (may be severe)
  • Diarrhea (may be severe)
  • Fatigue
  • Mucositis
  • Abdominal pain
  • Myelosuppression ± infection, bleeding (may be severe)
  • Rash, photosensitivity
  • Hand-foot syndrome
  • Pharyngolaryngeal dysesthesia
  • Edema
  • Alopecia
  • Anorexia
  • Constipation (diarrhea more common)
  • Electrolyte abnormalities
  • Injection site reaction
  • Hypersensitivity
  • Arterial thromboembolism
  • Venous thromboembolism
  • Hypersensitivity
  • Cardiotoxicity, arrhythmia
  • Hemolytic uremic syndrome
  • Nephrotoxicity
  • Pancreatitis
  • Pneumonitis
  • Rhabdomyolysis
  • PRES
  • Obstruction
  • Hemolysis
  • ↑ LFTS
  • Leucoencephalopathy
 
G - Interactions

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


  • Avoid concomitant use of drugs affecting hepatic metabolism (i.e. cimetidine) due to increased serum concentrations and toxicity of fluorouracil
  • Avoid metronidazole use as it may decrease the clearance of fluorouracil
  • Fluorouracil may increase phenytoin levels and toxicity; monitor levels and patient
  • Avoid thiazide diuretics as they may decrease renal excretion of fluorouracil
  • Warfarin clearance may be reduced.  Monitor INR closely and adjust warfarin dose as necessary
 
H - Drug Administration and Special Precautions

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


Drug Administration

Oxaliplatin:

  • Oxaliplatin should always be administered before fluorouracil.
  • May be mixed in 250-500 mL bag (D5W only - not NS, chloride containing or alkaline solutions, and should not be mixed with fluorouracil) and given 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 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 should be given prior to fluorouracil
  • Dilute in D5W and infuse IV over 120 minutes

 

Fluorouracil:

  • Slow push through sidearm of free-flowing IV (5% Dextrose, Normal Saline)
  • May be mixed in 50mL minibag (NS or D5W); infuse over 15 min.
  • Protect from light

 

Contraindications

  • Severe myelosuppression induced by prior chemotherapy or radiotherapy
  • Patients with poor nutritional state
  • Patients with potentially serious infections
  • Oxaliplatin is contraindicated in patients with hypersensitivity to the drug or to other platinum agents (e.g. cisplatin, carboplatin) and in patients with severe renal impairment (Clcr < 30 mL/min).

Other Warnings/Precautions

  • Patients should be warned about cold avoidance prior to treatment and ice for mucositis prophylaxis should not be used.
  • Oxaliplatin may result in dizziness or visual disturbrances (including transient vision loss) in some patients; patients should exercise caution in driving or operating machinery.
  • Use with extreme caution in patients who have undergone recent major surgery, with renal or hepatic impairment, widespread bone marrow involvement, or are suspected to have DPD deficiency
  • Avoid live vaccines; use may result in serious infections in immunocompromised patients.
 
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 treatment
  • Electrolytes, including magnesium; baseline and before each cycle
  • INR, if patient on anticoagulants; as clinically indicated
  • Liver function tests; baseline and before each cycle
  • Renal function tests; baseline and before each cycle
  • 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
Days 1, 15, 29: 4.5 hours; Days 8, 22, 36: 2.5 hours
Pharmacy Workload (average time per visit)
22.062 minutes
Nursing Workload (average time per visit)
47.917 minutes
 
K - References

Fluorouracil, oxaliplatin, leucovorin drug monographs, Cancer Care Ontario.

Kuebler JP, Wieand S, O’Connel MJ et al. Oxaliplatin Combined With Weekly Bolus Fluorouracil and Leucovorin As Surgical Adjuvant Chemotherapy for Stage II and III Colon Cancer: Results From NSABP C-07. JCO 25(16) June 2007: 2198-2204.

 


August 2019 removed archived PEBC guideline link


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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.