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A discussion and review of the evidence for the dose of Leucovorin® (calcium folinate or folinic acid) when being administered with fluorouracil.

Leucovorin® (LV) enhances the activity of fluorouracil (5-FU) by stabilising the ternary complex formed between thymidylate synthase, 5 fluorodeoxyuridine monophosphate (5FdUMP), an active metabolite of 5-FU and 5,10 methylene- tetrahydrofolate (a metabolite of FA).

Preclinical studies suggest cellular concentrations of 10 micromol/L of LV are required for optimal activity of LV with 5-FU. Priest et al showed a plasma concentration of 10 micromol/L of LV can be achieved at doses greater or equal to 125 mg/m2 of LV.r However, this may vary given differences in bioavailability between patients. LV on its own does not inhibit thymidylate synthase. The terminal half-life of LV is 6.2 hours.r

There is no convincing evidence on the optimum dose of LV to use when administered with 5-FU.

1. Cancer Care Ontario’s Leucovorin® in colorectal cancer evidence summary found insufficient evidence to recommend deviation from clinical trial doses of LV based on the literature included.r

2. The QUASAR collaborative group found similar 3-year survival rates between 25 mg low dose folinic acid (FA) and 175 mg high dose FA (given as bolus) with 5-FU 270 mg/m2, 71% versus 70.1% respectively (difference 0.9%, [SD 1.3]). The 3-year risk of recurrence was also similar between low and high dose FA, 35.8% and 36% respectively (difference 0.2%, [SD 1.6]).r

3. Reynolds et al found similar overall survival in patients treated with 20mg/m2 low dose FA compared to 400mg/m2 high dose FA, 14.2 months (95%CI: 10.0-20.5) and 18.7 months (95%CI: 14.0-23.4) respectively.r 

4. Shank et al found no statistically significant difference in progression free survival in patients treated with 50mg FA compared to 200-500mg/m2 BSA adjusted FA, 9.5months (95%CI: 4.8-14.2) and 8.8 months (95%CI: 6.2-11.4) respectively (P=0.254).r Median overall survival was also not statistically significant between the two groups, 28 months with 50 mg FA compared to 36.2 months with BSA adjusted FA (P=0.923).

5. Buroker et al found no difference in therapeutic effectiveness between 20mg/m2 low dose FA and 500mg/m2 high dose FA, objective tumour response was 35% versus 31% respectively (P=0.51), and median survival of 9.3 months versus 10.7 months respectively.r

Conclusion: Given the lack of evidence on the optimum dose of LV when administered with 5-FU, and evidence suggesting similar therapeutic efficacy, a flat dose of 50 mg LV has been included in relevant eviQ colorectal and upper gastrointestinal protocols based on reference committee consensus. The dose of LV employed in the clinical trial supporting the evidence for the regimen has also been included in the eviQ protocol.

While every effort has been made to ensure the accuracy of the content at the time of publication, the Cancer Institute NSW does not accept any liability, with respect to loss, damage, injury or expense arising from any such errors or omission in the contents of this work. Any reference to specific pharmaceuticals and/or medical products as examples does not imply endorsement of any of these products. Use is subject to eviQ’s disclaimer available at

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25 Jun 2019