Baird, Susan F.

Forster, Victoria J.

Halsey, Christina

Mair, Shona

Skinner, Roderick

van Delft, Frederik W.

English

Enlighten: Publications

 
 
 
 
Forster, V. J., van Delft, F. W., Baird, S. F., Mair, S., Skinner, R. and 
Halsey, C. (2017) Reply: Methotrexate neurotoxicity due to drug 
interactions: an inadequate folinic acid effect. Cancer Chemotherapy and 
Pharmacology, 79(4), pp. 841-842. (doi:10.1007/s00280-017-3270-4) 
 
This is the author’s final accepted version. 
 
There may be differences between this version and the published version. 
You are advised to consult the publisher’s version if you wish to cite from 
it. 
 
 
 
 
http://eprints.gla.ac.uk/138243/ 
     
 
 
 
 
 
 
Deposited on: 14 March 2017 
 
 
 
 
 
 
 
 
 
 
 
 
Enlighten – Research publications by members of the University of Glasgow 
http://eprints.gla.ac.uk 
Reply: Methotrexate neurotoxicity due to drug interactions: 
an inadequate folinic acid effect 
 
Victoria J. Forster1 · Frederik W. van Delft1 · Susan F. Baird2 · Shona Mair2 · 
Roderick Skinner3 · Christina Halsey4 
 
* Victoria J. Forster 
victoria.forster@newcastle.ac.uk 
1 Paul O’Gorman Building, Northern Institute for Cancer 
Research, Newcastle University, Newcastle upon Tyne, 
NE2 4HH, UK 
2 Royal Hospital for Sick Children, Edinburgh, UK 
3 Great North Children’s Hospital, Newcastle upon Tyne, UK 
4 Institute of Cancer Sciences, University of Glasgow, 
Glasgow, UK 
 
We thank Professor Cohen for his reply and his interesting points regarding the possible role 
of inadequate folinic acid rescue in contributing to neurotoxic side-effects of methotrexate. We 
can confirm that the patient reported in our article [1] had not received any previous exposure 
to any systemic methotrexate (oral or intravenous) even at low dose. In addition, the other 
published article on this possible interaction with nitrous oxide [2] reported a patient 
developing symptoms early during induction therapy on a protocol with a standard 3-drug 
induction (vincristine, asparaginase and corticosteroids). Therefore, concomitant systemic 
methotrexate appears not to be a contributing factor in either of these reported cases.  
As pointed out by Prof Cohen the recent article by Krull et al [3] indicates, for the first time in 
acute lymphoblastic leukaemia (ALL), a direct association between methotrexate plasma levels 
(area under the curve) and adverse long-term neurocognitive outcomes.  The role of folinic 
acid rescue in prevention of neurotoxic side effects remains speculative [4,5]  and has never 
been tested in a randomised trial. In addition, the impact of over-rescue on leukaemic relapse 
is still uncertain [6,7] and differences in scheduling and concomitant chemotherapy as well as 
individual pharmacogenomics are all likely to play a part. 
It is worth noting that nitrous oxide irreversibly inactivates vitamin B12 - a co-factor for 
methionine synthase- rather than directly interfering with Methotrexate induced inhibition of 
dihydrofolate reductase [8]. Since methionine synthase activity is required for homocysteine 
to methionine conversion,  it may be that, in the presence of low/inactive B12, the efficacy of 
folinic acid rescue in reducing neurotoxic symptoms related to high homocysteine [9] and/or 
low methionine is more limited.  In other words, even in the presence of adequate folinic acid 
rescue, the conversion of homocysteine to methionine may still be impaired due to low 
methionine synthase activity. However, to our knowledge this has never been tested 
experimentally. 
In summary, further studies are clearly needed to investigate the optimal dosing of both 
methotrexate and folinic acid rescue in order to balance efficacy and toxicity. Yet, we still 
believe that the most effective way of reducing this potential drug interaction is to limit 
exposure to nitrous oxide, especially as a number of safe non-toxic alternative anaesthetic 
agents are in routine use.   
 
 
 
 
1. Forster VJ, van Delft FW, Baird SF, Mair S, Skinner R, Halsey C. Drug interactions 
may be important risk factors for methotrexate neurotoxicity, particularly in pediatric 
leukemia patients. Cancer Chemother Pharmacol. 2016;78(5):1093-1096. 
2. Lobel U, Trah J, Escherich G. Severe neurotoxicity following intrathecal 
methotrexate with nitrous oxide sedation in a child with acute lymphoblastic leukemia. 
Pediatr Blood Cancer. 2015;62(3):539-541. 
3. Krull KR, Cheung YT, Liu W, et al. Chemotherapy Pharmacodynamics and 
Neuroimaging and Neurocognitive Outcomes in Long-Term Survivors of Childhood Acute 
Lymphoblastic Leukemia. J Clin Oncol. 2016;34(22):2644-2653. 
4. Cohen IJ. Inadequate folinic acid rescue after methotrexate causing neurocognitive 
and neuroradiological central nervous system late effects in children with acute lymphatic 
leukemia. J Pediatr Hematol Oncol. 2014;36(6):501. 
5. Cohen IJ. Challenging the clinical relevance of folinic acid over rescue after high dose 
methotrexate (HDMTX). Med Hypotheses. 2013;81(5):942-947. 
6. Skarby TV, Anderson H, Heldrup J, et al. High leucovorin doses during high-dose 
methotrexate treatment may reduce the cure rate in childhood acute lymphoblastic leukemia. 
Leukemia. 2006;20(11):1955-1962. 
7. Borsi JD, Sagen E, Romslo I, Moe PJ. Rescue after intermediate and high-dose 
methotrexate: background, rationale, and current practice. Pediatr Hematol Oncol. 
1990;7(4):347-363. 
8. Eger EI, 2nd. Nitrous oxide/N20. New York: Elsevier. 1985. 
9. Cole PD, Beckwith KA, Vijayanathan V, Roychowdhury S, Smith AK, Kamen BA. 
Folate homeostasis in cerebrospinal fluid during therapy for acute lymphoblastic leukemia. 
Pediatr Neurol. 2009;40(1):34-41. 
 


Reply: Methotrexate neurotoxicity due to drug interactions: an inadequate folinic acid effect

Victoria J. Forster

Frederik W. van Delft

Susan F. Baird

Shona Mair

Roderick Skinner

Christina Halsey

Crossref

Cancer Chemotherapy and Pharmacology

Enlighten

    Forster, V. J., van Delft, F. W., Baird, S. F., Mair, S., Skinner, R. and Halsey, C. (2017) Reply: Methotrexate neurotoxicity due to drug interactions: an inadequate folinic acid effect. Cancer Chemotherapy and Pharmacology, 79(4), pp. 841-842. (doi:10.1007/s00280-017-3270-4)  This is the author’s final accepted version.  There may be differences between this version and the published version. You are advised to consult the publisher’s version if you wish to cite from it.     http://eprints.gla.ac.uk/138243/            Deposited on: 14 March 2017             Enlighten – Research publications by members of the University of Glasgow http://eprints.gla.ac.uk Reply: Methotrexate neurotoxicity due to drug interactions: an inadequate folinic acid effect  Victoria J. Forster1 · Frederik W. van Delft1 · Susan F. Baird2 · Shona Mair2 · Roderick Skinner3 · Christina Halsey4  * Victoria J. Forster victoria.forster@newcastle.ac.uk 1 Paul O’Gorman Building, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK 2 Royal Hospital for Sick Children, Edinburgh, UK 3 Great North Children’s Hospital, Newcastle upon Tyne, UK 4 Institute of Cancer Sciences, University of Glasgow, Glasgow, UK  We thank Professor Cohen for his reply and his interesting points regarding the possible role of inadequate folinic acid rescue in contributing to neurotoxic side-effects of methotrexate. We can confirm that the patient reported in our article [1] had not received any previous exposure to any systemic methotrexate (oral or intravenous) even at low dose. In addition, the other published article on this possible interaction with nitrous oxide [2] reported a patient developing symptoms early during induction therapy on a protocol with a standard 3-drug induction (vincristine, asparaginase and corticosteroids). Therefore, concomitant systemic methotrexate appears not to be a contributing factor in either of these reported cases.  As pointed out by Prof Cohen the recent article by Krull et al [3] indicates, for the first time in acute lymphoblastic leukaemia (ALL), a direct association between methotrexate plasma levels (area under the curve) and adverse long-term neurocognitive outcomes.  The role of folinic acid rescue in prevention of neurotoxic side effects remains speculative [4,5]  and has never been tested in a randomised trial. In addition, the impact of over-rescue on leukaemic relapse is still uncertain [6,7] and differences in scheduling and concomitant chemotherapy as well as individual pharmacogenomics are all likely to play a part. It is worth noting that nitrous oxide irreversibly inactivates vitamin B12 - a co-factor for methionine synthase- rather than directly interfering with Methotrexate induced inhibition of dihydrofolate reductase [8]. Since methionine synthase activity is required for homocysteine to methionine conversion,  it may be that, in the presence of low/inactive B12, the efficacy of folinic acid rescue in reducing neurotoxic symptoms related to high homocysteine [9] and/or low methionine is more limited.  In other words, even in the presence of adequate folinic acid rescue, the conversion of homocysteine to methionine may still be impaired due to low methionine synthase activity. However, to our knowledge this has never been tested experimentally. In summary, further studies are clearly needed to investigate the optimal dosing of both methotrexate and folinic acid rescue in order to balance efficacy and toxicity. Yet, we still believe that the most effective way of reducing this potential drug interaction is to limit exposure to nitrous oxide, especially as a number of safe non-toxic alternative anaesthetic agents are in routine use.       1. Forster VJ, van Delft FW, Baird SF, Mair S, Skinner R, Halsey C. Drug interactions may be important risk factors for methotrexate neurotoxicity, particularly in pediatric leukemia patients. Cancer Chemother Pharmacol. 2016;78(5):1093-1096. 2. Lobel U, Trah J, Escherich G. Severe neurotoxicity following intrathecal methotrexate with nitrous oxide sedation in a child with acute lymphoblastic leukemia. Pediatr Blood Cancer. 2015;62(3):539-541. 3. Krull KR, Cheung YT, Liu W, et al. Chemotherapy Pharmacodynamics and Neuroimaging and Neurocognitive Outcomes in Long-Term Survivors of Childhood Acute Lymphoblastic Leukemia. J Clin Oncol. 2016;34(22):2644-2653. 4. Cohen IJ. Inadequate folinic acid rescue after methotrexate causing neurocognitive and neuroradiological central nervous system late effects in children with acute lymphatic leukemia. J Pediatr Hematol Oncol. 2014;36(6):501. 5. Cohen IJ. Challenging the clinical relevance of folinic acid over rescue after high dose methotrexate (HDMTX). Med Hypotheses. 2013;81(5):942-947. 6. Skarby TV, Anderson H, Heldrup J, et al. High leucovorin doses during high-dose methotrexate treatment may reduce the cure rate in childhood acute lymphoblastic leukemia. Leukemia. 2006;20(11):1955-1962. 7. Borsi JD, Sagen E, Romslo I, Moe PJ. Rescue after intermediate and high-dose methotrexate: background, rationale, and current practice. Pediatr Hematol Oncol. 1990;7(4):347-363. 8. Eger EI, 2nd. Nitrous oxide/N20. New York: Elsevier. 1985. 9. Cole PD, Beckwith KA, Vijayanathan V, Roychowdhury S, Smith AK, Kamen BA. Folate homeostasis in cerebrospinal fluid during therapy for acute lymphoblastic leukemia. Pediatr Neurol. 2009;40(1):34-41.  

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Reply: Methotrexate neurotoxicity due to drug interactions: an inadequate folinic acid effect

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