The literature listed below are independent of FivepHusion.

Clinical Studies

Folinic acid in colorectal cancer: esquire or fellow knight? Real-world results from a mono institutional, retrospective study.
Romano FJ, Barbato C, Biglietto M, Di Lauro V, Arundine D, Fiorentino R, Ambrosio F, Cammarota M, Chiurazzi B, Puglia L, Scagliarini S, Ruocco R, Mocerino C, Cerillo I, Brangi MF, Riccardi F. 2021. Oncotarget 12(3):221-229.
Description: In this comparative study, continuous co-infusion of 5-FU and sodium LV significantly improved patient progression-free survival compared to sequential administration.

A phase II randomized study of combined infusional leucovorin sodium and 5-FU versus the leucovorin calcium followed by 5-FU both in combination with irinotecan or oxaliplatin in patients with metastatic colorectal cancer.
Bleiberg H, Vandebroek A, Deleu I, Vergauwe P, Rezaei Kalantari H, D’Haens G, Paesmans M, Peeters M, Efira A, Humblet Y. 2012. Acta Gastro-Enterologica Belgica 75:14-21.
Description: In this comparative study, a continuous co-infusion of 5-FU and sodium LV significantly improved patient overall survival compared to sequential administration.

A simplified regimen of weekly high dose 5-fluorouracil and leucovorin as a 24-hour infusion in patients with advanced colorectal carcinoma.
Yang TS, Hsu KC, Chiang JM, Tang R, Chen JS, Changchien CR, Wang JY. 1999. Cancer 85(9):1925-1930.
Description: A continuous co-infusion of 5-FU and low-dose LV produced a response rate of 53% in chemotherapy-naïve patients; response rates of ~20-30% were typical of 5-FU/LV monotherapy at the time.

A phase II study of weekly 24-hour infusion of high-dose 5-fluorouracil and leucovorin (HDFL) in the treatment of recurrent or metastatic colorectal cancers.
Yeh KH, Cheng AL, Lin MT, Hong RL, Hsu CH, Lin JF, Chang KJ, Lee PH, Chen YC. 1997. Anticancer Research 17(5B):3867-3871.
Description: A continuous, diluted co-infusion of 5-FU and LV produced a response rate of 52% in first-line patients; response rates of ~20-30% were typical of 5-FU/LV monotherapy at the time.

A phase II study of weekly 24-hour infusion with high-dose fluorouracil with leucovorin in colorectal carcinoma.
Ardalan B, Chua L, Tian EM, Reddy R, Sridhar K, Benedetto P, Richman S, Legaspi A, Waldman S, Morrell L. 1991. Journal of Clinical Oncology 9(4):625-630.
Description: A continuous co-infusion of 5-FU and LV delivered via separate pumps produced a response rate of 58% in chemotherapy-naïve patients; response rates of ~20-30% were typical of 5-FU/LV monotherapy at the time. The median survival of these patients had not yet been reached by 22 months; a median survival of ~10-12 months was typical at that time.

Pre/Non-clinical Studies

Intracellular metabolism of 5-formyl tetrahydrofolate in human breast and colon cell lines.
Boarman DM, Allegra CJ. 1992. Cancer Research 52(1):36-44.
Description: This in vitro study demonstrated that folate polyglutamation is dependent on the duration of exposure to LV. Polyglutamation is an important determinant of folate affinity for thymidylate synthase – the 5-FU target enzyme – and intracellular retention.

Schedule-dependent enhancement of the cytotoxicity of fluoropyrimidines to human carcinoma cells in the presence of folinic acid.
Moran RG, Scanlon KL. 1991. Cancer Research 51(17):4618-4623.
Description: This in vitro study demonstrated that the cytotoxicity of 5-FU increases exponentially with a longer co-exposure to LV, with the most extensive enhancement between 24-48 hours of co-exposure.

Role of folylpolyglutamates in biochemical modulation of fluoropyrimidines by leucovorin.
Romanini A, Lin JT, Niedzwiecki D, Bunni M, Priest DG, Bertino JR. 1991. Cancer Research 51(3):789-793.
Description: This study indicates that the extent of folate polyglutamation influences 5-FU/LV cytotoxicity in vitro.

Relationship between dose rate of [6RS]Leucovorin administration, plasma concentrations of reduced folates, and pools of 5,10-methylenetetrahydrofolates and tetrahydrofolates in human colon adenocarcinoma xenografts.
Houghton JA, Williams LG, de Graaf SS, Cheshire PJ, Rodman JH, Maneval DC, Wainer IW, Jadaud P, Houghton PJ. 1990. Cancer Research 50(12):3493-3502.
Description: This in vivo study in mice models demonstrated that once the LV infusion has ended, folate pools are rapidly eliminated from both plasma and tumour. The extent of folate polyglutamation was also dependent on the duration of LV administration.

Effect of polyglutamylation of 5,10-methylenetetrahydrofolate on the binding of 5-fluoro-2′-deoxyuridylate to thymidylate synthase purified from a human colon adenocarcinoma xenograft.
Radparvar S, Houghton PJ, Houghton JA. 1989. Biochemical Pharmacology 38(2):335-342.
Description: This study demonstrated that polyglutamated folates are considerably more efficient at stabilising the thymidylate synthase enzymatic complex with 5-FU than folates with fewer glutamate residues.

Biochemical factors affecting the tightness of 5-fluorodeoxyuridylate binding to human thymidylate synthetase.
Lockshin A, Danenberg PV. 1981. Biochemical Pharmacology 30(3):247-257.
Description: This study demonstrated that stabilisation of the thymidylate synthase enzymatic complex is only transient, with the dissociation half-life being inversely proportional to the concentration of unbound folate cofactor, indicating that a continuous, excess supply of folate is necessary to maintain enzymatic inhibition by 5-FU.

The literature listed below are independent of FivepHusion.

Metastatic colorectal cancer: Advances in the folate-fluoropyrimidine chemotherapy backbone.
Glimelius B, Stintzing S, Marshall J, Yoshino T, de Gramont A. 2021. Cancer Treatment Reviews 98:102218.
Description: This review discusses the persistence of 5-FU/LV as the backbone of treatment for metastatic colorectal cancer at present and into the future, and discusses innovations – including Deflexifol™ – that aim to optimise it.

Pharmacokinetically guided dose adjustment of 5-fluorouracil: a rational approach to improving therapeutic outcomes.
Saif MW, Choma A, Salamone SJ, Chu E. 2009. Journal of the National Cancer Institute 101(22):1543-1552.
Description: This paper reviews the pharmacokinetics evidence indicating that ~40-60% of patients are underdosed with 5-FU, and that in these patients, higher doses of 5-FU than standardly administered can improve clinical outcomes.

Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: an updated meta-analysis.
Thirion P, Michiels S, Pignon JP, Buyse M, Braud AC, Carlson RW, O’Connell M, Sargent P, Piedbois P; Meta-Analysis Group in Cancer. 2004. Journal of Clinical Oncology 22(18):3766-3775.
Description: This seminal meta-analysis demonstrated that the addition of LV to 5-FU therapy doubled colorectal cancer tumour response rates (from 11% to 21%) and produced a small but statistically significant improvement in patient overall survival (from 10.5 to 11.7 months).

Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with bimonthly high-dose leucovorin and fluorouracil bolus plus continuous infusion for advanced colorectal cancer: a French intergroup study.
de Gramont A, Bosset JF, Milan C, Rougier P, Bouché O, Etienne PL, Morvan F, Louvet C, Guillot T, François E, Bedenne L. 1997. Journal of Clinical Oncology 15(2):808-815.
Description: This clinical trial demonstrated that 5-FU (+ LV) administered as a bolus followed by a prolonged infusion improved clinical outcomes and reduced Grade 3-4 toxicities compared to bolus administration alone. This administration schedule became the standard of care, and remains so today as “modified de Gramont”.

The literature listed below are independent of FivepHusion.

Clinical Studies

Phase I study of 5-fluorouracil in children and young adults with recurrent ependymoma.
Wright KD, Daryani VM, Turner DC, Onar-Thomas A, Boulos N, Orr BA, Gilbertson RJ, Stewart CF, Gajjar A. 2015. Neuro-Oncology 17(12):1620-1627.
Description: This phase I study demonstrated anti-tumour activity of standard, bolus 5-FU monotherapy in children and young adults with recurrent ependymoma.

Pre-Clinical Studies

Identification of FDA-approved oncology drugs with selective potency in high-risk childhood ependymoma.
Donson AM, Amani V, Warner EA, Griesinger AM, Witt DA, Levy JMM, Hoffman LM, Hankinson TC, Handler MH, Vibhakar R, Dorris K, Foreman NK. 2018. Molecular Cancer Therapeutics 17(9):1984-1994.
Description: In this large scale drug screen, 5-FU was found to have selective anti-tumour toxicity against paediatric ependymoma cell lines.

An integrated in vitro and in vivo high-throughput screen identifies treatment leads for ependymoma.
Atkinson JM, Shelat AA, Carcaboso AM, Kranenburg TA, Arnold LA, Boulos N, Wright K, Johnson RA, Poppleton H, Mohankumar KM, Féau C, Phoenix T, Gibson P, Zhu L, Tong Y, Eden C, Ellison DW, Priebe W, Koul D, Yung WK, Gajjar A, Stewart CF, Guy RK, Gilbertson RJ. 2011. Cancer Cell 20(3):384-399.
Description: In this high-throughput drug screen, 5-FU was found to have a strong and selective anti-tumour toxicity against ependymoma models.