Skip to main content
Top
Published in: Supportive Care in Cancer 2/2021

01-02-2021 | Cytostatic Therapy | Original Article

Neu-horizons: neuroprotection and therapeutic use of riluzole for the prevention of oxaliplatin-induced neuropathy—a randomised controlled trial

Authors: Terry Trinh, Susanna B. Park, Jenna Murray, Hannah Pickering, Cindy S.-Y. Lin, Andrew Martin, Michael Friedlander, Matthew C. Kiernan, David Goldstein, Arun V. Krishnan

Published in: Supportive Care in Cancer | Issue 2/2021

Login to get access

Abstract

Trial design

Peripheral neuropathy is a commonly reported adverse effect of oxaliplatin treatment, representing a significant limitation which may require discontinuation of effective therapy. The present study investigated the neuroprotective potential of riluzole in patients undergoing oxaliplatin treatment in a randomised-controlled trial comparing riluzole and placebo-control.

Methods

Fifty-two patients (17 females, 58.1 ± 12.7 years) receiving oxaliplatin treatment were randomised into either a treatment (50 mg riluzole) or lactose placebo group. The primary outcome measure was the total neuropathy score-reduced (TNSr). Secondary outcome measures include nerve excitability measures, 9-hole pegboard and FACT-GOG NTX questionnaire. Patients were assessed at baseline, pre-cycle 10 or 12, 4-week and 12-week post-treatment.

Results

Both the treatment and placebo groups developed objective and patient reported evidence of neurotoxicity over the course of oxaliplatin treatment, although there were no significant differences across any parameters between the two groups. However, across follow-up assessments, the treatment group experienced greater neuropathy, represented by a higher TNSr score at 4-week post-chemotherapy of 8.3 ± 2.7 compared with 4.6 ± 3.6 (p = 0.032) which was sustained at 12-week post-treatment (p = 0.089). Similarly, patients in the treatment group reported worse symptoms with a FACT-GOG NTX score of 37.4 ± 10.2 compared with 43.3 ± 7.4 (p = 0.02) in the placebo group at 4-week post-treatment.

Conclusion

This study is the first to provide an objective clinical investigation of riluzole in oxaliplatin-induced peripheral neuropathy employing both functional and neurophysiological measures. Although the recruitment target was not reached, the results do not show any benefit of riluzole in minimising neuropathy and may suggest that riluzole worsens neuropathy associated with oxaliplatin treatment.
Appendix
Available only for authorised users
Literature
4.
go back to reference Argyriou AA, Cavaletti G, Briani C, Velasco R, Bruna J, Campagnolo M, Alberti P, Bergamo F, Cortinovis D, Cazzaniga M, Santos C, Papadimitriou K, Kalofonos HP (2013) Clinical pattern and associations of oxaliplatin acute neurotoxicity: a prospective study in 170 patients with colorectal cancer. Cancer 119(2):438–444. https://doi.org/10.1002/cncr.27732CrossRefPubMed Argyriou AA, Cavaletti G, Briani C, Velasco R, Bruna J, Campagnolo M, Alberti P, Bergamo F, Cortinovis D, Cazzaniga M, Santos C, Papadimitriou K, Kalofonos HP (2013) Clinical pattern and associations of oxaliplatin acute neurotoxicity: a prospective study in 170 patients with colorectal cancer. Cancer 119(2):438–444. https://​doi.​org/​10.​1002/​cncr.​27732CrossRefPubMed
6.
go back to reference Velasco R, Bruna J, Briani C, Argyriou AA, Cavaletti G, Alberti P, Frigeni B, Cacciavillani M, Lonardi S, Cortinovis D, Cazzaniga M, Santos C, Kalofonos HP (2014) Early predictors of oxaliplatin-induced cumulative neuropathy in colorectal cancer patients. J Neurol Neurosurg Psychiatry 85(4):392–398. https://doi.org/10.1136/jnnp-2013-305334CrossRefPubMed Velasco R, Bruna J, Briani C, Argyriou AA, Cavaletti G, Alberti P, Frigeni B, Cacciavillani M, Lonardi S, Cortinovis D, Cazzaniga M, Santos C, Kalofonos HP (2014) Early predictors of oxaliplatin-induced cumulative neuropathy in colorectal cancer patients. J Neurol Neurosurg Psychiatry 85(4):392–398. https://​doi.​org/​10.​1136/​jnnp-2013-305334CrossRefPubMed
24.
go back to reference Poupon L, Lamoine S, Pereira V, Barriere DA, Lolignier S, Giraudet F, Aissouni Y, Meleine M, Prival L, Richard D, Kerckhove N, Authier N, Balayssac D, Eschalier A, Lazdunski M, Busserolles J (2018) Targeting the TREK-1 potassium channel via riluzole to eliminate the neuropathic and depressive-like effects of oxaliplatin. Neuropharmacology 140:43–61. https://doi.org/10.1016/j.neuropharm.2018.07.026CrossRefPubMed Poupon L, Lamoine S, Pereira V, Barriere DA, Lolignier S, Giraudet F, Aissouni Y, Meleine M, Prival L, Richard D, Kerckhove N, Authier N, Balayssac D, Eschalier A, Lazdunski M, Busserolles J (2018) Targeting the TREK-1 potassium channel via riluzole to eliminate the neuropathic and depressive-like effects of oxaliplatin. Neuropharmacology 140:43–61. https://​doi.​org/​10.​1016/​j.​neuropharm.​2018.​07.​026CrossRefPubMed
32.
go back to reference Calhoun EA, Welshman EE, Chang CH, Lurain JR, Fishman DA, Hunt TL, Cella D (2003). Psychometric evaluation of the functional assessment of cancer therapy/gynecologic oncology group-neurotoxicity (Fact/GOG-Ntx) questionnaire for patients receiving systemic chemotherapy. Int J Gynecol Cancer 13 (6):741–748. doi:https://doi.org/10.1111/j.1525-1438.2003.13603.x Calhoun EA, Welshman EE, Chang CH, Lurain JR, Fishman DA, Hunt TL, Cella D (2003). Psychometric evaluation of the functional assessment of cancer therapy/gynecologic oncology group-neurotoxicity (Fact/GOG-Ntx) questionnaire for patients receiving systemic chemotherapy. Int J Gynecol Cancer 13 (6):741–748. doi:https://​doi.​org/​10.​1111/​j.​1525-1438.​2003.​13603.​x
36.
go back to reference Huang CS, Song JH, Nagata K, Yeh JZ, Narahashi T (1997) Effects of the neuroprotective agent riluzole on the high voltage-activated calcium channels of rat dorsal root ganglion neurons. J Pharmacol Exp Ther 282(3):1280–1290PubMed Huang CS, Song JH, Nagata K, Yeh JZ, Narahashi T (1997) Effects of the neuroprotective agent riluzole on the high voltage-activated calcium channels of rat dorsal root ganglion neurons. J Pharmacol Exp Ther 282(3):1280–1290PubMed
37.
go back to reference Hebert T, Drapeau P, Pradier L, Dunn RJ (1994) Block of the rat brain IIA sodium channel alpha subunit by the neuroprotective drug riluzole. Mol Pharmacol 45(5):1055–1060PubMed Hebert T, Drapeau P, Pradier L, Dunn RJ (1994) Block of the rat brain IIA sodium channel alpha subunit by the neuroprotective drug riluzole. Mol Pharmacol 45(5):1055–1060PubMed
41.
go back to reference von Delius S, Eckel F, Wagenpfeil S, Mayr M, Stock K, Kullmann F, Obermeier F, Erdmann J, Schmelz R, Quasthoff S, Adelsberger H, Bredenkamp R, Schmid RM, Lersch C (2007) Carbamazepine for prevention of oxaliplatin-related neurotoxicity in patients with advanced colorectal cancer: final results of a randomised, controlled, multicenter phase II study. Investig New Drugs 25(2):173–180. https://doi.org/10.1007/s10637-006-9010-yCrossRef von Delius S, Eckel F, Wagenpfeil S, Mayr M, Stock K, Kullmann F, Obermeier F, Erdmann J, Schmelz R, Quasthoff S, Adelsberger H, Bredenkamp R, Schmid RM, Lersch C (2007) Carbamazepine for prevention of oxaliplatin-related neurotoxicity in patients with advanced colorectal cancer: final results of a randomised, controlled, multicenter phase II study. Investig New Drugs 25(2):173–180. https://​doi.​org/​10.​1007/​s10637-006-9010-yCrossRef
42.
go back to reference Gewandter JS, Brell J, Cavaletti G, Dougherty PM, Evans S, Howie L, McDermott MP, O'Mara A, Smith AG, Dastros-Pitei D, Gauthier LR, Haroutounian S, Jarpe M, Katz NP, Loprinzi C, Richardson P, Lavoie-Smith EM, Wen PY, Turk DC, Dworkin RH, Freeman R (2018) Trial designs for chemotherapy-induced peripheral neuropathy prevention: ACTTION recommendations. Neurology 91(9):403–413. https://doi.org/10.1212/WNL.0000000000006083CrossRefPubMedPubMedCentral Gewandter JS, Brell J, Cavaletti G, Dougherty PM, Evans S, Howie L, McDermott MP, O'Mara A, Smith AG, Dastros-Pitei D, Gauthier LR, Haroutounian S, Jarpe M, Katz NP, Loprinzi C, Richardson P, Lavoie-Smith EM, Wen PY, Turk DC, Dworkin RH, Freeman R (2018) Trial designs for chemotherapy-induced peripheral neuropathy prevention: ACTTION recommendations. Neurology 91(9):403–413. https://​doi.​org/​10.​1212/​WNL.​0000000000006083​CrossRefPubMedPubMedCentral
44.
go back to reference Hershman DL, Unger JM, Crew KD, Minasian LM, Awad D, Moinpour CM, Hansen L, Lew DL, Greenlee H, Fehrenbacher L, Wade JL 3rd, Wong SF, Hortobagyi GN, Meyskens FL, Albain KS (2013) Randomized double-blind placebo-controlled trial of acetyl-L-carnitine for the prevention of taxane-induced neuropathy in women undergoing adjuvant breast cancer therapy. J Clin Oncol 31(20):2627–2633. https://doi.org/10.1200/JCO.2012.44.8738CrossRefPubMedPubMedCentral Hershman DL, Unger JM, Crew KD, Minasian LM, Awad D, Moinpour CM, Hansen L, Lew DL, Greenlee H, Fehrenbacher L, Wade JL 3rd, Wong SF, Hortobagyi GN, Meyskens FL, Albain KS (2013) Randomized double-blind placebo-controlled trial of acetyl-L-carnitine for the prevention of taxane-induced neuropathy in women undergoing adjuvant breast cancer therapy. J Clin Oncol 31(20):2627–2633. https://​doi.​org/​10.​1200/​JCO.​2012.​44.​8738CrossRefPubMedPubMedCentral
45.
go back to reference Kerckhove N, Busserolles J, Stanbury T, Pereira B, Plence V, Bonnetain F, Krakowski I, Eschalier A, Pezet D, Balayssac D (2019). Effectiveness assessment of riluzole in the prevention of oxaliplatin-induced peripheral neuropathy: RILUZOX-01: protocol of a randomised, parallel, controlled, double-blind and multicentre study by the UNICANCER-AFSOS Supportive Care intergroup. BMJ Open 9 (6):e027770. doi:https://doi.org/10.1136/bmjopen-2018-027770 Kerckhove N, Busserolles J, Stanbury T, Pereira B, Plence V, Bonnetain F, Krakowski I, Eschalier A, Pezet D, Balayssac D (2019). Effectiveness assessment of riluzole in the prevention of oxaliplatin-induced peripheral neuropathy: RILUZOX-01: protocol of a randomised, parallel, controlled, double-blind and multicentre study by the UNICANCER-AFSOS Supportive Care intergroup. BMJ Open 9 (6):e027770. doi:https://​doi.​org/​10.​1136/​bmjopen-2018-027770
Metadata
Title
Neu-horizons: neuroprotection and therapeutic use of riluzole for the prevention of oxaliplatin-induced neuropathy—a randomised controlled trial
Authors
Terry Trinh
Susanna B. Park
Jenna Murray
Hannah Pickering
Cindy S.-Y. Lin
Andrew Martin
Michael Friedlander
Matthew C. Kiernan
David Goldstein
Arun V. Krishnan
Publication date
01-02-2021
Publisher
Springer Berlin Heidelberg
Published in
Supportive Care in Cancer / Issue 2/2021
Print ISSN: 0941-4355
Electronic ISSN: 1433-7339
DOI
https://doi.org/10.1007/s00520-020-05591-x

Other articles of this Issue 2/2021

Supportive Care in Cancer 2/2021 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine