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High-dose Methotrexate

CC BY-NC-ND 4.0 · Indian J Med Paediatr Oncol 2019; 40(03): 424-426

DOI: DOI: 10.4103/ijmpo.ijmpo_157_19

Author : Dhanushkodi, Manikandan

Abstract

High-dose methotrexate (HDMTX) is defined as methotrexate dose of ≥500 mg/m2. It is used in the treatment of acute lymphoblastic leukemia, osteosarcoma, and primary central nervous system lymphoma. Administration mandates adequate hydration; urine alkalinization; leucovorin rescue, monitoring of urine output, serum creatinine, and methotrexate levels. Delayed methotrexate clearance is managed by increasing hydration and leucovorin dose. Glucarpidase is the antidote for patients with renal toxicity. Studies from India have shown that HDMTX can be administered without monitoring of methotrexate levels with strict monitoring of urine pH, urine output, and serum creatinine and extended hydration and leucovorin doses.

Keywords

High-dose methotrexate - methotrexate levels - toxicity


Publication History

Received: 24 July 2019

Accepted: 25 July 2019

Article published online:
03 June 2021

© 2019. Indian Society of Medical and Paediatric Oncology. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).

Thieme Medical and Scientific Publishers Pvt. Ltd.
A-12, 2nd Floor, Sector 2, Noida-201301 UP, India


Abstract

High-dose methotrexate (HDMTX) is defined as methotrexate dose of ≥500 mg/m2. It is used in the treatment of acute lymphoblastic leukemia, osteosarcoma, and primary central nervous system lymphoma. Administration mandates adequate hydration; urine alkalinization; leucovorin rescue, monitoring of urine output, serum creatinine, and methotrexate levels. Delayed methotrexate clearance is managed by increasing hydration and leucovorin dose. Glucarpidase is the antidote for patients with renal toxicity. Studies from India have shown that HDMTX can be administered without monitoring of methotrexate levels with strict monitoring of urine pH, urine output, and serum creatinine and extended hydration and leucovorin doses.


Keywords

High-dose methotrexate - methotrexate levels - toxicity

Introduction

Methotrexate is a folate antagonist having anticancer, anti-inflammatory, and immunomodulatory properties. It is used in a wide range of malignancies as well as in psoriasis and rheumatoid arthritis. It can be delivered via oral, intramuscular, intravenous, and intrathecal route.


Mechanism of Action

Methotrexate enters the cells through a reduced folate carrier (RFC) and is polyglutamated. This competitively and reversibly inhibits dihydrofolate reductase, the enzyme that converts dihydrofolate to tetrahydrofolate. The lack of tetrahydrofolate inhibits DNA, RNA, and protein synthesis.[1] Methotrexate is most active against rapidly dividing cells during the S phase of a cell cycle.

Leucovorin (5-formyl-tetrahydrofolic acid) enters cells through the RFC and replenishes intracellular stores of tetrahydrofolate and attenuates the toxicity of high-dose methotrexate (HDMTX).[2]


Discovery

In 1947, Sydney Farber showed that aminopterin (folic acid analog) developed by Yellapragada Subbarao (Indian) induced remission in acute lymphoblastic leukemia (ALL). In 1956, animal studies showed that the therapeutic index for methotrexate was better than aminopterin.


Approval

Methotrexate is Food and Drug Administration approved for the treatment of malignancies including ALL, breast cancer, gestational trophoblastic disease, lung cancer, osteosarcoma, mycosis fungoides, and non-Hodgkin's lymphoma.


HDMTX Definition

It is defined as a dose of >500 mg/m2 delivered over 4–36 h duration and supplemented with leucovorin rescue to terminate the side effects of methotrexate. The maximum dose that has been tried is 33 g/m2 in ALL to avoid cranial irradiation.[3]


Uses

HDMTX is used in the treatment of ALL, osteosarcoma, and primary central nervous system lymphoma [Table 1].


Table 1

Clinical trials with high-dose methotrexate

Administration

  • Ensure baseline complete blood count and liver function is normal and creatinine clearance >60 ml/min. Any third-space fluid collection (ascites, pleural effusion) should be drained before starting HDMTX

  • As HDMTX is a low emetogenic drug, 5-HT3 antagonist alone is used to prevent nausea and vomiting

  • Serum creatinine, methotrexate levels, and urine output should be monitored to assess methotrexate clearance

  • Intravenous hydration (3 L/m2/day) should be started 6 h before starting methotrexate and continued until clearance of methotrexate levels

  • Strict monitoring of input/output chart is mandatory. Urine output should be at least 150 ml/m2/h before starting methotrexate

  • Methotrexate and its metabolites precipitate when urine pH is <5>7.0 by urine alkalinization until methotrexate levels fall <0 href="https://www.thieme-connect.com/products/ejournals/html/10.4103/ijmpo.ijmpo_157_19#JR_7" xss=removed>7] Sodium bicarbonate (40 mEq/L) should be supplemented with intravenous fluids

  • After methotrexate administration, plasma methotrexate levels should be measured at 24, 48, and 72 h after starting methotrexate and should be repeated until methotrexate levels fall <0>

  • Leucovorin (15 mg/m2 Q 6 hourly) should be started within 24 h of starting methotrexate until methotrexate levels are <0 href="https://www.thieme-connect.com/products/ejournals/html/10.4103/ijmpo.ijmpo_157_19#TB_2" xss=removed>Table 2].

Tumor

Study

HDMTX dose

Duration of HDMTX

Leucovorin dose

Time from methotrexate to leucovorin

HDMTX - High-dose methotrexate; CNS - Central nervous system; ALL - Acute lymphoblastic leukemia

All

Hill et al. MRC UKALL XI[4]

Age ≤4 years→6 g/m2
Age >4 years→8 g/m2

10% bolus, reminder over 23 h

15 mg/m2 every 3 h, then every 6 h until methotrexate levels <0>

36 h

Osteosarcoma

Souhami et al.
European Osteosarcoma
Intergroup[5]

Age <12>2
Age >12 years→12 g/m2

-

15 mg/m2 every 6 h orally for 10 doses

24 h

Primary CNS lymphoma

Batchelor et al. NABTT study[6]

8 g/m2

4 h

Pharmcokinetically guided until methotrexate levels <0>

24 h
Table 2

Leucovorin rescue schedule

icity

Acute renal toxicity can happen in 2%–12% of patients receiving HDMTX.[8] Nephrotoxicity is due to crystallization of methotrexate in the renal tubular epithelium. The risk factors include baseline renal dysfunction, volume depletion, acidic urine, use of nonsteroidal anti-inflammatory drugs (NSAIDs), and drug interaction. Furthermore, advanced age, low serum protein, higher dose, and 1st HDMTX have been associated with increased toxicity.[9] Genetic polymorphism that alters the metabolism of methotrexate can lead to toxicity.[10] Renal toxicity delays methotrexate clearance and causes myelosuppression, mucositis, skin toxicity, and hepatotoxicity. A study from Cancer Institute, Chennai, showed that 42 h methotrexate levels predicted delayed clearance and toxicity.[11] Change in the creatinine from the baseline after HDMTX predicts hematologic toxicity.[12] HDMTX up to 5 g/m2 can be safely administered without monitoring of methotrexate levels by extended hydration, additional leucovorin, and monitoring of serum creatinine and urine pH.[13]

When there is delayed clearance of methotrexate, hydration and leucovorin should be increased to prevent toxicity. In case of toxicity, glucarpidase (50 U/kg over 5 min) should be given along with leucovorin. This eliminates extracellular methotrexate by converting into nontoxic 4-deoxy-4-amino-N-10-methylpteroic acid. Glucarpidase is currently unavailable in India and needs to be imported. High-flux dialysis is an option if all the above measures fail.[14]

Hepatotoxicity is more common with oral methotrexate than with HDMTX. Risk factors are long-term methotrexate, consumption of alcohol, and hepatitis B and C infection. The other rare side effects include cortical blindness, hemiparesis, seizure, and pulmonary toxicity.

Practical Tips

  1. Third-space fluid collections such as ascites or pleural effusion should be drained before initiation of methotrexate[7]

  2. Drugs such as aspirin, cotrimoxazole, aminoglycosides, amphotericin, penicillin, NSAIDs, and proton pump inhibitors should be avoided while on HDMTX[1]

  3. Adequate hydration, urine alkalinization, leucovorin rescue, and monitoring of methotrexate levels help to prevent toxicity[7]

  4. If methotrexate levels are unavailable, monitoring of urine output, pH, and creatinine and twice-daily examination of mucous membrane can allow usage of HDMTX[15]

  5. Leucovorin should not be administered 2 h before or after administration of glucarpidase

  6. Within 48 h of administration of glucarpidase, only high-performance liquid chromatography method should be used to detect methotrexate levels.



    Conclusion

    HDMTX administration is feasible with adequate hydration; urine alkalinization; leucovorin rescue; and monitoring of urine output, serum creatinine, and methotrexate levels.

    Conflict of Interest

    There are no conflicts of interest

    • References

Clinical situation

Laboratory findings

Leucovorin dose and duration

IV - Intravenous

Normal methotrexate elimination

Serum methotrexate level <10>

15 mg IV q 6 hourly for 60 h (10 doses starting at 24 h after start of methotrexate infusion)

Delayed late methotrexate elimination

Serum methotrexate level >0.2 micromolar at 72 h, >0.05 micromolar at 96 h

Continue 15 mg IV q 6 hourly, until methotrexate level <0>

Delayed early methotrexate elimination/acute renal injury

Serum methotrexate level >50 micromolar at 24 h, >5 micromolar at 48 h >100% increase in serum creatinine level form baseline at 24 h

150 mg IV q 3 h, until methotrexate level <1>

  1.  Howard SC, McCormick J, Pui CH, Buddington RK, Harvey RD. Preventing and managing toxicities of high-dose methotrexate. Oncologist 2016; 21: 1471-82
  2.  Treon SP, Chabner BA. Concepts in use of high-dose methotrexate therapy. Clin Chem 1996; 42: 1322-9
  3.  Nathan PC, Whitcomb T, Wolters PL, Steinberg SM, Balis FM, Brouwers P. et al. Very high-dose methotrexate (33.6 g/m (2)) as central nervous system preventive therapy for childhood acute lymphoblastic leukemia: Results of national cancer institute/Children's cancer group trials CCG-191P, CCG-134P and CCG-144P. Leuk Lymphoma 2006; 47: 2488-504
  4.  Hill FG, Richards S, Gibson B, Hann I, Lilleyman J, Kinsey S. et al. Successful treatment without cranial radiotherapy of children receiving intensified chemotherapy for acute lymphoblastic leukaemia: Results of the risk-stratified randomized central nervous system treatment trial MRC UKALL XI (ISRC TN 16757172). Br J Haematol 2004; 124: 33-46
  5.  Souhami RL, Craft AW, Van der Eijken JW, Nooij M, Spooner D, Bramwell VH. et al. Randomised trial of two regimens of chemotherapy in operable osteosarcoma: A study of the European osteosarcoma intergroup. Lancet 1997; 350: 911-7
  6.  Batchelor T, Carson K, O'Neill A, Grossman SA, Alavi J, New P. et al. Treatment of primary CNS lymphoma with methotrexate and deferred radiotherapy: A report of NABTT 96-07. J Clin Oncol 2003; 21: 1044-9
  7.  Al-Quteimat OM, Al-Badaineh MA. Practical issues with high dose methotrexate therapy. Saudi Pharm J 2014; 22: 385-7
  8.  Widemann BC, Balis FM, Kim A, Boron M, Jayaprakash N, Shalabi A. et al. Glucarpidase, leucovorin, and thymidine for high-dose methotrexate-induced renal dysfunction: Clinical and pharmacologic factors affecting outcome. J Clin Oncol 2010; 28: 3979-86
  9.  Cheng DH, Lu H, Liu TT, Zou XQ, Pang HM. Identification of risk factors in high-dose methotrexate-induced acute kidney injury in childhood acute lymphoblastic leukemia. Chemotherapy 2018; 63: 101-7
  10.  Park JA, Shin HY. Influence of genetic polymorphisms in the folate pathway on toxicity after high-dose methotrexate treatment in pediatric osteosarcoma. Blood Res 2016; 51: 50-7
  11.  Tiwari P, Ganesan P, Radhakrishnan V, Arivalazhan R, Ganesa TS, Dhanushkodi M. Prospective evaluation of the toxicity profile, and predictors of toxicity of high dose methotrexate in patients of acute lymphoblastic leukemia/lymphoma. Pediatr Hematol Oncol J 2018; 3: 1-5
  12.  Tiwari P, Thomas MK, Pathania S, Dhawan D, Gupta YK, Vishnubhatla S. et al. Serum creatinine versus plasma methotrexate levels to predict toxicities in children receiving high-dose methotrexate. Pediatr Hematol Oncol 2015; 32: 576-84
  13.  Vaishnavi K, Bansal D, Trehan A, Jain R, Attri SV. Improving the safety of high-dose methotrexate for children with hematologic cancers in settings without access to MTX levels using extended hydration and additional leucovorin. Pediatr Blood Cancer 2018; 65: e27241
  14.  Wall SM, Johansen MJ, Molony DA, DuBose Jr. TD, Jaffe N, Madden T. et al. Effective clearance of methotrexate using high-flux hemodialysis membranes. Am J Kidney Dis 1996; 28: 846-54
  15.  Howard SC, Pedrosa M, Lins M, Pedrosa A, Pui CH, Ribeiro RC. et al. Establishment of a pediatric oncology program and outcomes of childhood acute lymphoblastic leukemia in a resource-poor area. JAMA 2004; 291: 2471-5

Address for correspondence

Dr. Manikandan Dhanushkodi
Cancer Institute (WIA)
38, Sardar Patel Road, Chennai - 600 036, Tamil Nadu
India   

Publication History

Received: 24 July 2019

Accepted: 25 July 2019

Article published online:
03 June 2021

© 2019. Indian Society of Medical and Paediatric Oncology. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).

Thieme Medical and Scientific Publishers Pvt. Ltd.
A-12, 2nd Floor, Sector 2, Noida-201301 UP, India

  1.  Howard SC, McCormick J, Pui CH, Buddington RK, Harvey RD. Preventing and managing toxicities of high-dose methotrexate. Oncologist 2016; 21: 1471-82
  2.  Treon SP, Chabner BA. Concepts in use of high-dose methotrexate therapy. Clin Chem 1996; 42: 1322-9
  3.  Nathan PC, Whitcomb T, Wolters PL, Steinberg SM, Balis FM, Brouwers P. et al. Very high-dose methotrexate (33.6 g/m (2)) as central nervous system preventive therapy for childhood acute lymphoblastic leukemia: Results of national cancer institute/Children's cancer group trials CCG-191P, CCG-134P and CCG-144P. Leuk Lymphoma 2006; 47: 2488-504
  4.  Hill FG, Richards S, Gibson B, Hann I, Lilleyman J, Kinsey S. et al. Successful treatment without cranial radiotherapy of children receiving intensified chemotherapy for acute lymphoblastic leukaemia: Results of the risk-stratified randomized central nervous system treatment trial MRC UKALL XI (ISRC TN 16757172). Br J Haematol 2004; 124: 33-46
  5.  Souhami RL, Craft AW, Van der Eijken JW, Nooij M, Spooner D, Bramwell VH. et al. Randomised trial of two regimens of chemotherapy in operable osteosarcoma: A study of the European osteosarcoma intergroup. Lancet 1997; 350: 911-7
  6.  Batchelor T, Carson K, O'Neill A, Grossman SA, Alavi J, New P. et al. Treatment of primary CNS lymphoma with methotrexate and deferred radiotherapy: A report of NABTT 96-07. J Clin Oncol 2003; 21: 1044-9
  7.  Al-Quteimat OM, Al-Badaineh MA. Practical issues with high dose methotrexate therapy. Saudi Pharm J 2014; 22: 385-7
  8.  Widemann BC, Balis FM, Kim A, Boron M, Jayaprakash N, Shalabi A. et al. Glucarpidase, leucovorin, and thymidine for high-dose methotrexate-induced renal dysfunction: Clinical and pharmacologic factors affecting outcome. J Clin Oncol 2010; 28: 3979-86
  9.  Cheng DH, Lu H, Liu TT, Zou XQ, Pang HM. Identification of risk factors in high-dose methotrexate-induced acute kidney injury in childhood acute lymphoblastic leukemia. Chemotherapy 2018; 63: 101-7
  10.  Park JA, Shin HY. Influence of genetic polymorphisms in the folate pathway on toxicity after high-dose methotrexate treatment in pediatric osteosarcoma. Blood Res 2016; 51: 50-7
  11.  Tiwari P, Ganesan P, Radhakrishnan V, Arivalazhan R, Ganesa TS, Dhanushkodi M. Prospective evaluation of the toxicity profile, and predictors of toxicity of high dose methotrexate in patients of acute lymphoblastic leukemia/lymphoma. Pediatr Hematol Oncol J 2018; 3: 1-5
  12.  Tiwari P, Thomas MK, Pathania S, Dhawan D, Gupta YK, Vishnubhatla S. et al. Serum creatinine versus plasma methotrexate levels to predict toxicities in children receiving high-dose methotrexate. Pediatr Hematol Oncol 2015; 32: 576-84
  13.  Vaishnavi K, Bansal D, Trehan A, Jain R, Attri SV. Improving the safety of high-dose methotrexate for children with hematologic cancers in settings without access to MTX levels using extended hydration and additional leucovorin. Pediatr Blood Cancer 2018; 65: e27241
  14.  Wall SM, Johansen MJ, Molony DA, DuBose Jr. TD, Jaffe N, Madden T. et al. Effective clearance of methotrexate using high-flux hemodialysis membranes. Am J Kidney Dis 1996; 28: 846-54
  15.  Howard SC, Pedrosa M, Lins M, Pedrosa A, Pui CH, Ribeiro RC. et al. Establishment of a pediatric oncology program and outcomes of childhood acute lymphoblastic leukemia in a resource-poor area. JAMA 2004; 291: 2471-5

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