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FULCVR(RT-GAST)
Gastrointestinal - Gastric / Stomach
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.
Adjuvant combined chemoradiotherapy for patients with resectable gastric cancer
Cycle 1:
| leucovorin | 20 mg /m²/day | IV | Days 1 to 5 |
| fluorouracil | 425 mg /m²/day | IV | Days 1 to 5 |
|
28-day cycle
Cycle 2 (with radiation): |
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| fluorouracil | 200 mg /m²/day | IV continuous infusion over 24 hours | during radiotherapy |
|
Cycles 3 † and 4: |
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| leucovorin | 20 mg /m²/day | IV | Days 1 to 5 |
| fluorouracil | 425 mg /m²/day | IV | Days 1 to 5 |
|
Q28 Days † Start new cycle 1 month after the end of radiotherapy
Alternative Schedule 1: Cycle 1: |
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| leucovorin | 400 mg /m² | IV | Days 1 and 15 |
| fluorouracil | 400 mg /m² | IV | Days 1 and 15 |
| fluorouracil | 2400 mg /m² | IV continuous infusion over 46 hours (total dose) | Days 1 and 15 |
|
28-day cycle Cycle 2 (With Radiation): |
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| fluorouracil | 225 mg /m²/day | IV continuous infusion over 24 hours | during radiotherapy |
|
Cycles 3 † and 4: |
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| leucovorin | 400 mg /m² | IV | Days 1 and 15 |
| fluorouracil | 400 mg /m² | IV | Days 1 and 15 |
| fluorouracil | 2400 mg /m² | IV continuous infusion over 46 hours (total dose) | Days 1 and 15 |
|
Q 28 Days
ALTERNATIVE SCHEDULE #2: Cycle 1: |
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| leucovorin | 20 mg /m²/day | IV | Days 1 to 5 |
| fluorouracil | 425 mg /m²/day | IV | Days 1 to 5 |
|
28-day cycle
Cycle 2 and 3 (with radiation): |
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| leucovorin | 20 mg /m²/day | IV | Days 1 to 3 or 4* |
| fluorouracil | 400 mg /m²/day | IV | Days 1 to 3 or 4* |
|
Q 28 Days *Give on first 4 days AND last 3 days of radiotherapy
|
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| leucovorin | 20 mg /m²/day | IV | Days 1 to 5 |
| fluorouracil | 425 mg /m²/day | IV | Days 1 to 5 |
|
Q 28 Days |
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Low
Low
Other Supportive Care:
May advise patients to suck on ice chips during bolus injection, to reduce stomatitis.
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
Leucovorin: No adjustment required.
Fluorouracil:
|
Toxicity or Counts (x 109/L) |
During Cycle |
For Next cycle
|
|
Platelets < 80 or AGC < 1.5 |
Hold* |
May consider ↓ |
|
Bleeding, febrile neutropenia |
Hold* |
↓ by 25% |
|
≥ grade 3 GI |
Hold* |
↓ by 25% |
| Toxicity or Counts (x 109/L) (continued) | During Cycle | For Next cycle |
|
CNS |
Hold* |
↓ by 25% |
|
Cardiac |
Hold* |
Consider discontinuing |
|
* Do not retreat until AGC ≥ 1.5 x 109/L , platelets ≥ 100 x 109/L and organ toxicity ≤ grade 2. With severe toxicity, consider testing for DPD deficiency prior to rechallenge. |
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Hepatic Impairment
Leucovorin: No adjustment required.
Consider dose reduction of fluorouracil with moderate to severe hepatic impairment.
Suggested:
|
Bilirubin |
|
AST/ALT |
Fluorouracil (% previous dose) |
|
< 2 x ULN |
and |
3-5 x ULN |
75 % |
|
2-4 x ULN |
or |
5-10 x ULN |
50-75% |
|
≥ 4 x ULN |
or |
≥ 10 x ULN |
Discontinue |
Renal Impairment
Fluorouracil: No adjustment required, although reduction may be considered with severe renal insufficiency.
Leucovorin: No adjustment required.
Dosage in the Elderly
[leucovorin]
[fluorouracil]
Refer to fluorouracil, leucovorin drug monograph(s) for additional details of adverse effects
Bolus 5-FU regimens have more myelosuppression and GI effects but less hand-foot Syndrome, compared to prolonged infusions.
|
Most Common Side Effects |
Less Common Side Effects, but may be Severe or Life-Threatening |
|
|
Refer to fluorouracil, leucovorin drug monograph(s) for additional details
- Fluorouracil is a known radiosensitizer. Patients should be carefully monitored for gastrointestinal toxicity when they are receiving concurrent 5FU-Radiation therapy.
- 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
Refer to fluorouracil, leucovorin drug monograph(s) for additional details
Administration:
Leucovorin
- Doses ≤100mg may be given by IV push through sidearm of free flowing IV (5% Dextrose, Normal Saline or 2/3-1/3). The injection must not exceed 160mg/min of leucovorin (due to calcium content).
- May be mixed in 50mL Normal Saline or 5% Dextrose minibag (doses up to 500mg) or 100mL minibag (doses >500mg) or in 100mL fluid in graduated administration set (5% Dextrose, Normal Saline or 2/3-1/3); Give over 15 minutes.
- Cryodesiccated powder reconstituted with Bacteriostatic Water for Injection containing benzyl alcohol should only be used at doses below 10 mg/m2
- Leucovorin should not be mixed in the same infusion as 5-fluorouracil as a precipitate may form.
- Keep refrigerated; protect from light.
Fluorouracil
IV PUSH OR INTERMITTENT INFUSION:
- 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.
IV CONTINUOUS INFUSION:
- Continuous infusion using CADD infusion pump, or similar device
- Infuse through central venous access device, if available
- Infusion volume and duration depend on protocol.
- Protect from light
- Infuse through patent peripheral venous catheter, if infusion for only 3-5 days; Inspect peripheral infusion sites daily and replace if evidence of irritation or extravasation
Special Precautions:
Contraindications:
- patients with poor nutritional state
- patients with depressed bone marrow function (prior pelvic irradiation / marrow infiltration)
- patients with potentially serious infections
- patients with known hypersensitivity to the drug or any of its excipients
Other Warnings/Precautions:
- 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.
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
- Liver function tests; baseline and before each cycle
- Renal function tests; baseline and before each cycle
- Clinical toxicity assessment and grading of stomatitis, diarrhea, bleeding, infection, local site toxicity, skin effects (rash or hand-foot-syndrome), cardiovascular or ophthalmic effects.; at each visit
-
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
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André T, Quinaux E, Louvet C, et al. Phase III study comparing a semimonthly with a monthly regimen of fluorouracil and leucovorin as adjuvant treatment for stage II and III colon cancer patients: final results of GERCOR C96.1. J Clin Oncol 2007 Aug 20;25(24):3732-8.
Fluorouracil and leucovorin drug monographs, Cancer Care Ontario.
Macdonald JS, Smalley SR, Benedetti J, et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med. 2001 Sep 6; 345(10): 725-30.
Martínez-Lago N, Vieito-Villar M, Vidal-Insua Y, et al. Adjuvant treatment with infusional 5-fluorouracil in high risk adenocarcinoma of the stomach or gastroesophageal junction. Clin Transl Oncol 2015 Jul 2. [Epub ahead of print]
NCCN Guidelines: Gastric Cancer. Version 3, 2015.
November 2017 Changed standard regimen and alternative #2 schedule, included cycle frequency for post-chemoradiation cycles
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.
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