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FOLFIRINOX

Cancer Type: Gastrointestinal, Pancreas  Intent: Palliative
Regimen Category: Evidence-Informed
Funding:
New Drug Funding Program
    Oxaliplatin and Irinotecan - Advanced Pancreatic Cancer (FOLFIRINOX)
A - Regimen Name

FOLFIRINOX Regimen
Folinic Acid (Leucovorin)-Fluorouracil-Irinotecan-Oxaliplatin


Disease Site
Gastrointestinal - Pancreas

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

First-line treatment of locally advanced unresectable or metastatic pancreatic adenocarcinoma in patients with ECOG status of 0 to 1 and bilirubin < 1.5 x ULN. Clinical trials excluded patients > 75 years or with significant cardiac disease or poor organ function.

Note: FOLFIRINOX will not be funded if a patient has previously progressed on GEMCNPAC.


Supplementary Public Funding

oxaliplatin
New Drug Funding Program (Oxaliplatin and Irinotecan - Advanced Pancreatic Cancer (FOLFIRINOX))

 
B - Drug Regimen

oxaliplatin
85 mg /m² IV over 2 hours Day 1
THEN,
leucovorin
400 mg /m² IV over 2 hours Day 1
30 minutes after starting leucovorin, give:
irinotecan
180 mg /m² IV over 90 minutes, concurrently with with leucovorin Day 1
fluorouracil
*
400 mg /m² IV bolus, after leucovorin Day 1
THEN,
fluorouracil
2400 mg /m² IV continuous infusion over 46 hours Start on Day 1

* may be omitted if toxicity of concern

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C - Cycle Frequency

REPEAT EVERY 14 DAYS

Continue until disease progression or unacceptable toxicity; in the clinical trial 12 cycles were recommended for responding patients, while the median number of cycles was 10 (range 1-47).

 
D - Premedication and Supportive Measures

Antiemetic Regimen:

Moderate

Other Supportive Care:

  • Irinotecan - Cholinergic adverse effects (early diarrhea)
  • Unless contraindicated, atropine 0.25-1mg IV/SC may be given for cholinergic adverse effects (early diarrhea)
  • Prophylactic atropine may be considered in patients experiencing cholinergic symptoms
  • Diarrhea (abdominal cramp = diarrhea) may be severe and delayed with irinotecan; use loperamide 4mg at the onset of diarrhea, then 2mg q2h until patient is diarrhea-free for 12 hours
  • Filgrastim use may be considered as secondary prophylaxis for neutropenia.
 
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

Do not start new cycle until platelets ≥ 75 x 109/L and ANC ≥ 1.5 x 109/L, recovery from diarrhea (to baseline without loperamide for at least 24 hours), and other non-hematologic toxicities have recovered to ≤grade 2.

Doses should be adjusted based on the worst preceding toxicity. Do not re-escalate dose if reduced for toxicity. Discontinue the regimen if toxicity recurs after 2 dose reductions.

Leucovorin dose is not reduced for toxicity; however it should be omitted if fluorouracil is omitted.

Dose Levels: 

 

Drug Regular Dose level
(mg/m2)
Dose level -1
(mg/m2)
Dose level -2
(mg/m2)
Irinotecan 180 150 --
Oxaliplatin 85 60 --
Fluorouracil bolus 400 300 200
Fluorouracil infusion 2400 1800 1200

(Refer to dose modification table on the next page)

 

 

 

Dose Modifications:

 
Toxicity
Occurrence
Irinotecana,b
Oxaliplatina,b
Flurouracila,b
Febrile neutropenia OR
Grade 4 ANC > 7 d OR
Delay 1-2 weeks for ≥ Grade 1 ANC
1st
↓ 1 dose level
No change
 
2nd
As above
↓ 1 dose level

Thrombocytopenic bleeding OR

≥ grade 3 platelets OR

Delay 1-2 weeks for grade 2 platelets

1st
No change
↓ 1 dose level
↓ 1 dose level
2nd
 
↓ 1 dose level
As above

Diarrhea ≥ grade 3 OR

Diarrhea with fever or ≥ Grade 3 ANC

1st
↓ 1 dose level
No change
Discontinue bolus
2nd
As above
↓ 1 dose level
As above & ↓ 1 dose level
Grade 3 or 4 mucositis or hand-foot syndrome - No change No change ↓ 1 dose level

Grade 2 persistent neurotoxicity

-
No change
↓ 1 dose level
No change

Grade 2 other non-hematological

-
Consider ↓
Consider ↓
Consider ↓

Grade 3 neurotoxicity (recovers prior to next cycle)

-
No change
↓ 1 dose level
No change

Grade 3 other non-hematological

-
↓ 1 dose level
↓ 1 dose level
↓ 1 dose level
Pneumonitis Any Discontinue Discontinue Discontinue

Grade 3 persistent neurotoxicity
OR
Grade 4 neurotoxicity

 

Any
Discontinue
Discontinue Discontinue
Toxicity (Continued) Occurrence Irinotecana,b Oxaliplatina,b Flurouracila,b

Grade 4 other non-hematological 

OR

RPLS

OR

Hemolytic uremic syndrome or any signs of microangiopathic hemolytic anemia

Any Discontinue Discontinue Discontinue

Pharyngolaryngeal dysesthesia

 -
 -
↑ infusion to 6 hours
-
aDo not treat until ANC ≥ 1.5 x 109/L, platelets ≥ 75 x 109/L, diarrhea resolved to baseline and other toxicity ≤ grade 2.  Do not re-escalate dose if reduced for toxicity. 
bDiscontinue the regimen if toxicity recurs after 2 dose reductions or if cycle delayed for > 2 weeks.



Hepatic Impairment

Transaminases
Bilirubin^
Irinotecan
Oxaliplatin
5FU
 
1-1.5 X ULN or Gilbert's
Consider ↓
No change
No change
 > 3 X ULN*
>1.5-4 X ULN
Omit
No change
No change
 
> 4 XULN
Omit
No info found
Omit
* or 5 X ULN with liver metastases

^ If bilirubin ↑, consider investigating for reversible causes such as biliary obstruction and reevaluate after stent.

 

Renal Impairment

Creatinine Clearance (mL/min)

oxaliplatin

(% previous dose)

fluorouracil

(% previous dose)

irinotecan

(% previous dose)

>60
No change
No change
No change

>30-60                         

Caution
No change
No change
10-30
Discontinue
Consider dose reduction
Caution
<10
Discontinue
Consider dose reduction
Caution

 
F - Adverse Effects

Refer to oxaliplatin, leucovorin, irinotecan, 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
  • Fatigue
  • Abdominal pain/cramping
  • Alopecia
  • ↑ LFTs (may be severe)
  • Diarrhea (early and late, may be severe)
  • Anorexia
  • Mucositis
  • Constipation
  • Edema
  • Eye disorders
  • Myelosuppression ± infection, bleeding (may be severe)
  • Photosensitivity
  • Rash
  • Hand-foot syndrome

       

  • Arterial thromboembolism
  • Hypersensitivity
  • Cerebellar syndrome
  • GI obstruction
  • GI perforation
  • Cardiotoxicity
  • Hemolytic uremic syndrome
  • Hepatotoxicity
  • Renal failure
  • Pancreatitis
  • Pneumonitis
  • Rhabdomyolysis
  • Seizure
  • Venous thromboembolism
 
G - Interactions
Refer to oxaliplatin, leucovorin, irinotecan, fluorouracil drug monograph(s) for additional details
 
H - Drug Administration and Special Precautions

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

 
I - Recommended Clinical Monitoring

Recommended Clinical Monitoring

  • CBC; baseline and regular
  • Liver and renal function tests; baseline and regular
  • Electrolytes, including magnesium; baseline and regular
  • Monitor INR closely for patients on warfarin
  • Routine toxicity rating of diarrhea and other GI effects, cholingeric symptoms, hypersensitivity, pneumonitis, bleeding, infection, dehydration, pancreatitis, neurological, thromboembolism, hand-foot syndrome, cardiac toxicity and fatigue.
  • 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 regular

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J - Administrative Information

Approximate Patient Visit
4.5 hours
Pharmacy Workload (average time per visit)
44.043 minutes
Nursing Workload (average time per visit)
75.833 minutes
 
K - References

Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011;364:1817-25.

October 2017 re-link NDFP form


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L - Other Notes

Diarrhea can be severe, with either immediate or delayed onset. Patients must be instructed in the use of Loperamide as treatment for diarrhea, and must have a supply of this drug upon starting Irinotecan treatments.

The phase III PRODIGE 4/ACCORD 11 trial (Conroy et al.) has demonstrated significant improvement in median overall survival, median PFS and objective response as compared to gemcitabine. Despite the toxicities, FOLFIRINOX has shown greater clinical benefit than gemcitabine when coupled with adequate patient selection and effective management of toxic side effects.

 
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.