1. Home
  2. Additional clinical information

Folinic acid (calcium folinate or Leucovorin®): low dose or high dose

This document is a quick and concise evidence-based summary to provide additional information, instruction, or guidance to complement a treatment protocol or clinical resource document. 

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.

On this page
Expand all Collapse all Back to top
[%id%]
[%title%]
[%abstract%]

Bibliography

Evans, R. M., J. D. Laskin and M. T. Hakala. 1981. "Effect of excess folates and deoxyinosine on the activity and site of action of 5-fluorouracil." Cancer Res. 41(9 Pt 1):3288-3295.

The present study concerns the basis of the effects of high levels of folinic acid (CF) and deoxyinosine (dIno) on the potency and site of action of 5-fluorouracil (FUra) in mouse sarcoma (Sarcoma 180) and human carcinoma cells (Hep-2) in vitro. Sarcoma 180 cells are 50 times more sensitive to FUra than are Hep-2 cells, and thymidylate synthetase (dTMP synthetase) inhibition is growth limiting in Sarcoma 180 but not in Hep-2. Cells were exposed for 3 hr to varied concentrations of FUra alone or in combination with 10 µm CF and/or 1 mm dIno, and the following parameters were determined: (a) the subsequent growth (5 or 6 days) in FUra-free Medium 1640 with or without either 30 µm thymidine or 1 mm 2′-deoxyuridine (dUrd); (b) metabolism of FUra; (c) activity of dTMP synthetase in cell extracts; and (d) incorporation of [2-14C]dUrd at 0, 3, 6, 24, and 48 hr following FUra exposure.

In both cell lines, dIno increased the cellular content of unbound 5-fluoro-2′-deoxyuridine-5′-monophosphate up to 100 µm and the inhibition of dTMP synthetase. The potency of FUra, as measured by growth inhibition, was increased only against Sarcoma 180 and not against Hep-2. A very rapid recovery of enzyme activity occurred after dIno, and dTMP synthetase inhibition did not become growth limiting for Hep-2.

In both cell lines, 10 µm CF (1000 times more than required for growth) potentiated 3-fold the growth inhibition by FUra. This excess CF did not affect the extent of dTMP synthetase inhibition when measured immediately after FUra. Instead, the potentiating effect of CF is due to the stabilization of the enzyme-5-fluoro-2′-deoxyuridine-5′-monophosphate complex as evidenced by (a) a marked decrease in the ability of 1 mm dUrd to rescue Sarcoma 180 cells after treatment with FUra or Hep-2 cells after treatment with 5-fluoro-2′-deoxyuridine, without effect on the rescue with 2′-deoxythymidine and (b) a marked slow-down in the spontaneous recovery of dTMP synthetase activity after FUra or after FUra and dIno. In all conditions, the recovery of dTMP synthetase activity reached a limit at 6 hr after FUra removal. An impressive correlation was observed in Sarcoma 180 cells between the dTMP synthetase activities (measured by dUrd incorporation), which were reached 6 hr after FUra removal, and growth, which was measured at 5 days.

Effects identical to those of 10 µm CF were obtained with 300 µm folic acid or 10 µm N5-methyltetrahydrofolic acid. A maximum potentiation of growth inhibition (10-fold) occurred after combinations of FUra with excess folates and dIno.

It appears that the rate of recovery of dTMP synthetase activity plays a more significant role in the potency and site of action of FUra than does the amount of 5-fluoro-2′-deoxyuridine-5′-monophosphate which is formed and that this recovery can be greatly retarded with an excess of vitamins such as folate or CF.

Moran, R. G. and K. L. Scanlon. 1991. "Schedule-dependent enhancement of the cytotoxicity of fluoropyrimidines to human carcinoma cells in the presence of folinic acid." Cancer Res. 51(17):4618-4623.

Previous studies from this laboratory indicated that the cytotoxic effects of the fluoropyrimidines on mouse leukemic cells are substantially augmented by folinic acid but that these effects are underestimated in growth inhibition experiments. These results have now been extended to two human tumor cell lines, the WiDr colorectal and T-24 bladder carcinoma cells. In both cell lines, the presence of folinic acid in the medium substantially enhanced the cytotoxicity of a 72-h exposure to either 5-fluorouracil (FUra) or 5-fluoro-2'-deoxyuridine. Folinic acid concentration-response curves for enhancement of the cytotoxicity of FUra to WiDr cells were broad but indicated that response was not maximal until at least 10 microM. Likewise, increased length of exposure to 10 microM folinic acid continuously enhanced the cytotoxicity of a 72-h treatment with FUra, but substantial enhancement was observed even after a 2-h exposure to folinate, and there was a diminished increment of cytotoxicity after 24-h exposure to folinic acid. Surprisingly, folinic acid augmentation of the cytotoxicity of a brief exposure to FUra (4 h) was minimal but enhancement of FUra cytotoxicity became much more pronounced with intervals of exposure to FUra of greater than or equal to 24 h. If these results can be mimicked in vivo without undue host toxicity, our experiments suggest that a substantial improvement in the therapeutic activity of FUra plus folinate would result from prolonged exposure to both agents

Beck, A., M. C. Etienne, S. Cheradame, et al. 1994. "Wide range for optimal concentration of folinic acid in fluorouracil modulation--experimental data on human tumour cell lines." Eur.J.Cancer. 30A(10):1522-1526.

The clinical use of the fluorouracil (FU)-folinic acid (FA) combination is hampered by the still open choice of the optimal schedule, with marked controversy as concerns the optimal FA dose. This in vitro study on FU-FA combinations in 17 human cancer cell lines, representative of tumour types responding to FU-FA treatment, reassesses the notion of the optimal FA concentration. Cells were exposed for 5 days to various FU-FA concentrations (0.07-77 microM, 14 concentrations, for FU; and 0.0025-100 microM for FA). The growth inhibition was assessed by the MTT test. The investigated cell lines exhibited FU IC50 ranging from 0.4 to 38.9 microM (median 3.7 microM). In six out of 17 cell lines investigated, the addition of FA did not result in a substantial enhancement of FU cytotoxicity (group 1). For the remaining 11 cell lines responding to FA supplementation (group 2), the maximal enhancement factor ranged from 3 to 8, meaning that in the presence of optimal FA concentration, the efficient FU concentration (IC50) was reduced by between 3 and 8 as compared to the efficient FU concentration without FA supplementation. For cell lines responding to FA supplementation, the optimal FA concentrations ranged from 10(-7) to 4 x 10(-4) M (4000-fold range) with a median value at 9.6 x 10(-7) M. Distribution of cell doubling time was not significantly different between group 1 and group 2. In contrast, the FU IC50 were significantly different (P = 0.02) between group 1 (median 7.4 microM) and group 2 (median 2.2 microM), thus indicating that cell lines with the greatest FU cytotoxicity enhancement by FA were those intrinsically sensitive to FU and vice versa

Version 3

Date Summary of changes
31/05/2017

Transferred to new eviQ website. Version number change to V.2.

Previous website ID: 25
06/11/2018 Review and update of content. Version number changed to V.3.
20/10/2022

Clinical information document reviewed electronically by Medical Oncology Reference Committee. No changes. Next review in 4 years.

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. While eviQ endeavours to link to reliable sources that provide accurate information, eviQ and the Cancer Institute NSW do not endorse or accept responsibility for the accuracy, currency, reliability or correctness of the content of linked external information source. Use is subject to eviQ’s disclaimer available at www.eviQ.org.au

Send feedback for this page

Last reviewed:
Review due:

The currency of this information is guaranteed only up until the date of printing, for any updates please check:

https://www.eviq.org.au/p/3065

19 Apr 2024