Received: 26 May 2021 Revised: 29 September 2021 Accepted: 15 October 2021

DOI: 10.1111/bcp.15134

GUIDELINES

Medication therapy of high-dose methotrexate: An

evidence-based practice guideline of the Division of
Therapeutic Drug Monitoring, Chinese Pharmacological
Society

Zaiwei Song1,2,3 | Yang Hu1,2,3 | Shuang Liu1,2,3 | Guanru Wang1,2,3 |

Suodi Zhai1,2,3 | Xianglin Zhang4 | Youping Li5 | Guanhua Du6 |
Yuankai Shi7 | Yaolong Chen8 | Mei Dong9 | Ruichen Guo10 | Wei Guo11 |
Hongbing Huang12 | Xiaojun Huang13 | Hongmei Jing14 | Xiaoyan Ke14 |
Guohui Li15 | Liyan Miao16 | Xiaohui Niu17 | Feng Qiu18 | Jingnan Shen19 |
Jingyan Tang20 | Tianyou Wang21 | Xiaoling Wang22 | Zhuo Wang23 |
Jiuhong Wu24 | Siyan Zhan25,26 | Bikui Zhang27 | Lingli Zhang28 |
Yanhua Zhang29 | Wei Zhang30 | Limei Zhao31 | Libo Zhao22 | Jiancun Zhen30 |
Huyong Zheng21 | Zhu Zhu32 | Dan Jiang1,2,3 | Zhencheng Huang1,2,3 |
Zhiyuan Tan1,2,3 | Qiaonan Lin1,2,3 | Rongsheng Zhao1,2,3
1
Department of Pharmacy, Peking University Third Hospital, Beijing, China
2
Institute for Drug Evaluation, Peking University Health Science Center, Beijing, China
3
Therapeutic Drug Monitoring and Clinical Toxicology Center, Peking University, Beijing, China
4
Department of Pharmacy, China-Japan Friendship Hospital, Beijing, China
5
Chinese Evidence-Based Medicine Center, West China Hospital, Sichuan University, Chengdu, China
6
Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
7
Department of Medical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, National Cancer Center/National
Clinical Research Center for Cancer, Beijing, China
8
Evidence-Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
9
Department of Pharmacy, Harbin Medical University Cancer Hospital, Harbin, China
10
Institute of Clinical Pharmacology, Qilu Hospital of Shandong University, Jinan, China
11
Musculoskeletal Tumor Center, Peking University People's Hospital, Beijing, China
12
Department of Pharmacy, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
13
Peking University Institute of Hematology, Peking University People's Hospital, National Clinical Research Center for Hematologic Disease, Beijing, China
14
Department of Hematology, Peking University Third Hospital, Beijing, China
15
Department of Pharmacy, Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, National Cancer Center/National Clinical
Research Center for Cancer, Beijing, China
16
Department of Clinical Pharmacology, First Affiliated Hospital of Soochow University, Suzhou, China
17
Department of Orthopedic Oncology, Beijing Jishuitan Hospital and Fourth Medical College of Peking University, Beijing, China
18
Department of Pharmacy, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
19
Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China

The authors confirm that the PI for this paper is Rongsheng Zhao and that he had direct clinical responsibility for patients included in the study investigating the patients' willingness on
individualized medication of high-dose methotrexate.

2456 © 2021 British Pharmacological Society wileyonlinelibrary.com/journal/bcp Br J Clin Pharmacol. 2022;88:2456–2472.

SONG ET AL. 2457

20
Department of Hematology/Oncology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Key Lab of Pediatric Hematology &
Oncology of China Ministry of Health, Shanghai, China
21
Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China
22
Department of Pharmacy, Beijing Children's Hospital, Capital Medical University, Beijing, China
23
Department of Pharmacy, Shanghai Changhai Hospital, Second Military Medical University, Shanghai, China
24
Pharmacy Department, The 306th Hospital of PLA, Beijing, China
25
Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
26
Research Center of Clinical Epidemiology, Peking University Third Hospital, Beijing, China
27
Department of Pharmacy, The Second Xiangya Hospital of Central South University, Changsha, China
28
Department of Pharmacy/Evidence-Based Pharmacy Centre, West China Second University Hospital, Sichuan University, Chengdu, China
29
Department of Pharmacy, Peking University Cancer Hospital and Institute, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education),
Beijing, China
30
Department of Pharmacy, Jishuitan Hospital and Fourth Medical College of Peking University, Beijing, China
31
Department of Pharmacy, Shengjing Hospital of China Medical University, Shenyang, China
32
Department of Pharmacy, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China

Correspondence
Professor Rongsheng Zhao, Department of
Pharmacy, Peking University Third Hospital,
49 North Garden Rd., Haidian District, Beijing,
China.
Email: zhaorongsheng@bjmu.edu.cn
Funding information
National Natural Science Foundation of China
(NSFC), Grant/Award Number: 72074005;
Division of Therapeutic Drug Monitoring,
Chinese Pharmacological Society
Aims: A lot of medication risks related to high-dose methotrexate (HDMTX) therapy
still remain to be identified and standardized. This study aims to establish an
evidence-based practice guideline for individualized medication of HDMTX.
Methods: The practice guideline was launched by the Division of Therapeutic Drug
Monitoring, Chinese Pharmacological Society. The guideline was developed following
the WHO handbook for guideline development and the methodology of evidence-
based medicine (EBM). The guideline was initially registered in the International
Practice Guidelines Registry Platform (IPGRP-2017CN021). Systematic reviews were
conducted to synthesize available evidence. A multicentre cross-sectional study was
conducted using questionnaires to evaluate patients' perception and willingness
concerning individualized medication of HDMTX. The Grading of Recommendations
Assessment, Development, and Evaluation (GRADE) approach was used to rate the
quality of evidence and to grade the strength of recommendations.
Results: Multidisciplinary working groups were included in this guideline, including
clinicians, pharmacists, methodologists, pharmacologists and pharmacoeconomic
specialists. A total of 124 patients were involved to integrate patient values and pref-
erences. Finally, the guideline presents 28 recommendations, regarding evaluation
prior to administration (renal function, liver function, pleural effusion, comedications,
genetic testing), pre-treatment and routine dosing regimen, therapeutic drug monitor-
ing (necessity, method, timing, target concentration), leucovorin rescue (initial timing,
dosage regimen and optimization), and management of toxicities. Of these, 12 are
strong recommendations.
Conclusions: We developed an evidence-based practice guideline with respect to
HDMTX medication using a rigorous and multidisciplinary approach. This guideline
provides comprehensive and practical recommendations involving the whole process
of HDMTX administration to health care providers.

KEYWORDS
GRADE, guideline, methotrexate, therapeutic drug monitoring
2458
1 | I N T RO DU CT I O N
Methotrexate (MTX) is a folic acid antagonist with anti-proliferative
and anti-inflammatory properties, which has been used in the treat-
ment of various proliferative or immune disorders.1 High-dose metho-
trexate (HDMTX) is commonly defined as an intravenous dose greater
22
than 500 mg/m . HDMTX is recommended as an essential compo-
nent of chemotherapy for acute lymphoblastic leukaemia (ALL), non-
Hodgkin lymphoma (NHL) and osteosarcoma in clinical guidelines.3–5
Currently, although breakthroughs have been made in the complex
treatment of ALL, NHL and osteosarcoma, HDMTX still plays a key
2,6
role and is established as the first-line drug.
However, a lot of medication issues and risks during HDMTX
therapy still remain to be identified and standardized. First, patients
differ largely in their response to treatment regarding HDMTX
pharmacokinetics and toxicities, even when given the identical dose
of MTX.7,8 The plasma concentration and individual response depend
on multiple factors,9 and therapeutic drug monitoring (TDM) is
required. Second, HDMTX must be given with a series of supportive
care, including hydration, urinary alkalization, urine pH monitoring,
TDM and leucovorin rescue.10 Moreover, the MTX dosage regimen,
TDM criteria and supportive care protocol differ greatly across
tumour types and medical institutions. Therefore, serious and life-
threatening toxicity can occur in patients, leading to treatment
interruption and discontinuation, dose reduction, poor prognosis and
even death.2,11
To promote TDM implementation and individualized medication
of HDMTX, the Division of TDM of the Chinese Pharmacological
Society launched the clinical practice guideline Medication Therapy of
High-Dose Methotrexate. We intend to provide evidence-based recom-
mendations regarding the whole process of HDMTX administration to
health care providers.
2 | METHODS
We developed this guideline following the methodology
recommended by the WHO Handbook for guideline development12
and using the Appraisal of Guidelines for Research and Evaluation
(AGREE II).13 The latest definition of the Institute of Medicine (IOM)14
and the checklist of guideline 2.0 by the Canadian Medical
Association15 were followed. The final guideline was drafted
according to the Reporting Items for Practice Guidelines in Healthcare
(RIGHT).16 The whole development process is shown in Figure 1.
2.1 | Sponsor and supporters
This work was initiated and supported by the Division of TDM of the
Chinese Pharmaceutical Society. The Chinese Evidence-based
Medicine Center, Chinese Cochrane Center, and Chinese GRADE
Center provided methodological support.
SONG ET AL.
2.2 | Registration and protocol
This guideline has been registered on the International Practice
Guideline Registry Platform (IPGRP) with No. IPGRP-2017CN021
(http://www.guidelines-registry.cn).17 The protocol was drafted and
published.18
2.3 | Scope
This guideline focuses on the HDMTX medication (intravenous dose
greater than 500 mg/m2) in patients with haematological malignancy
or osteosarcoma. The primary target audiences are haematology
clinicians, bone oncologists, clinical pharmacologists, pharmacists,
nurses and the general population. Other health care professionals
and policy makers involved in the management of haematological
malignancy or osteosarcoma can also benefit from this guideline.
2.4 | Guideline working group
The following four groups were formed to guide the development of
the guideline (Supplementary Table S1):
1. Steering committee, consisting of two chief clinical pharmacy
experts (Suodi Zhai, Xianglin Zhang), one chief pharmacologist
(Guanhua Du), one chief clinical expert (Yuankai Shi), and one chief
methodological expert (Youping Li). They were responsible for the
top-level design of the guideline, making final decisions at each
stage, and controlling the entire process. Finally, they led the writ-
ing of the final draft of the guideline.18,19
2. Consensus panel, consisting of 26 multidisciplinary specialists:
13 clinical pharmacy specialists, three adult haematology special-
ists, three paediatric haematology specialists, three bone oncology
specialists, three methodologists and one pharmacoeconomic
specialist. The panel was responsible for determining the clinical
questions, voting for recommendations and building consen-
sus.18,19
3. Evidence synthesis team, consisting of eight pharmacists or
students who had been trained in evidence-based medicine. The
team was responsible for collecting clinical questions, retrieving,
evaluating, synthesizing and grading of evidence, conducting
systematic reviews, and formulating the summary of finding tables
and the recommendation decision tables.18,19
4. External review group, consisting of 45 first-line health care
professionals (27 clinicians, nine nurses, nine pharmacists) and
three patients or their families who had received treatment with
HDMTX.18,19
2.5 | Ethical considerations
All members of the steering committee and consensus panel com-
pleted a conflict-of-interest form before joining the guideline working
SONG ET AL.
F I G U R E 1 Development process of
Medication Therapy of High-Dose Methotrexate:
An Evidence-Based Practice Guideline
groups.20 No relevant financial conflicts of interest was identified.
The investigation of patient's values and preferences was approved
by the Peking University Institutional Review Board (PUIRB)
(No. IRB00001052–18023).
2.6 | Formulation of clinical questions
In the beginning, the initial draft of clinical questions was collected by
pre-retrieving literature and conducting group discussion and individ-
ual interviews with experienced clinicians, pharmacists and nurses in
the department of haematology or bone oncology. Subsequently,
a three-round Delphi vote was performed to frame the clinical
questions. Finally, 23 clinical questions were included and defined.21
2459
2.7 | Evidence syntheses/systematic review and
grading
To answer the included clinical questions, evidence was thoroughly
searched, and systematic reviews were conducted for each question
following the PICO framework. Databases including MEDLINE (Ovid),
EMBASE (Ovid), Clinical Trials.gov, Chinese National Knowledge
Infrastructure (CNKI), WANFANG Database and Chinese Biomedical
Literature Database (CBM) were searched. All databases were initially
searched from their inception until 8 June 2020. The languages were
limited to English and Chinese. For each systematic review, two
members of the evidence synthesis team independently extracted
data and assessed the quality of studies.
2460
The quality of systematic reviews/meta-analyses was assessed
using the Assessing the Methodological Quality of Systematic Reviews
(AMSTAR) tool,22,23 the quality of RCTs using the Cochrane Collabora-
tion tool,24 the quality of cohort studies or case–control studies using
25
the Newcastle-Ottawa Scale (NOS), and the quality of case reports
or case series using the Joanna Briggs Institute Critical Appraisal (JBI)
tools.26 Disagreements were resolved by discussion or consultation
with a third researcher. Meta-analyses of available studies were
conducted using RevMan 5.3 (Cochrane Collaboration). The Grading
of Recommendations Assessment, Development, and Evaluation
(GRADE) approach was applied to rate the quality of evidence and
27,28
determine the strength of recommendations.
2.8 | Investigation of patient's values and
preferences
Identifying patient priorities and preferences for care is important in
developing clinical practice guidelines.14 A multicentre cross-sectional
study involving patients with osteosarcoma or haematological
malignancy in seven hospitals was conducted by questionnaire to
evaluate the perception and willingness on gene detection and TDM
of HDMTX. All patients and children's guardians voluntarily accepted
the survey and provided informed consent forms. SPSS24.0 software
was used to conduct subgroup analysis of patient willingness and to
analyse the ranking of factors influencing patients' decision-making.
Among the 124 patients or children's guardians included, 106
(85.48%) and 117 (94.35%) patients agreed on gene detection and
TDM, respectively. The ranking of factors influencing patients'
decisions was clinical efficacy (the most important), safety, comfort
and cost (the least important).29
2.9 | Formulation of recommendations
For each clinical question, the evidence synthesis team developed an
evidence summary and GRADE decision table to provide a clear
description of benefits and harms. The certainty of the body of
evidence was graded as high (Level A), moderate (Level B), low
(Level C), very low (Level D), or expert opinion (no clinical study was
27,28,30
available). The consensus panel fully considered
magnitude of benefits and harms, the quality of evidence, resource
implications and feasibility, and underlying patients' values and
preferences.
Then, a three-round Delphi vote was used during the consensus
meeting for recommendations. The strength of recommendations
was graded as strong (Class 1) or weak (Class 2). All of 28 recommen-
dations reached consensus in the first round (12 strong recommenda-
tions and 16 weak recommendations), with the consensus rate of
100%.31 Finally, the draft of the recommendations was sent to first-
line health care professionals (27 clinicians, nine nurses, nine pharma-
cists) and three patients or their families for external review. The
guideline steering committee finalized the guideline in response to
comments from external reviewers and approved the
recommendations.
SONG ET AL.
2.10 | Reporting of the guideline
The recommendations were reported according to the Reporting
Items for Practice Guidelines in Healthcare (RIGHT) statement.16
2.11 | Nomenclature of targets and ligands
Key protein targets and ligands in this article are hyperlinked to
corresponding entries in http://www.guidetopharmacology.org, and
are permanently archived in the Concise Guide to PHARMACOLOGY
2019/20.31
3 | RE SU LT S
In the end, 28 recommendations involving the entire process of
HDMTX medication were formulated, including evaluation prior to
administration, routine dosing regimens, therapeutic drug monitoring,
leucovorin rescue and management of toxicities.31 The recommenda-
tion framework is shown in Figure 2.
3.1 | Evaluation prior to administration
3.1.1 | Is it necessary to test kidney function before
HDMTX administration?
Recommendation 1
We recommend to routinely test renal function before administra-
tion, and take it as one of the considerations for individualized
dose adjustment (strong recommendation, low-quality evidence).
Remarks: Renal function indicators include but are not limited to
glomerular filtration rate (GFR), creatinine clearance (Ccr), and serum
creatinine (Scr).
Rationale
Ninety percent of MTX is excreted in urine in its original form.
HDMTX-induced renal dysfunction is believed to be mediated by the
the precipitation of MTX and its metabolite 7-OH-MTX in the renal
tubules or via a direct toxic effect of MTX on the renal tubules.32
Acute kidney injury (AKI) develops in 2–12% of patients, and it
aggravates the delayed excretion, leads to drug accumulation, and
then causes systemic toxic reactions.2 The clinical guidance for
children and adolescents with ALL or osteosarcoma33,34 provide a
method to adjust the dose based on baseline renal function, as shown
in Table 1.
Evidence summary
The systematic review (Supplementary Table S2) included four cohort
studies. Testing renal function and adjusting the dose before
administration significantly reduced the liver toxicity (RR = 0.41,
final 95% CI = 0.17–0.97), gastrointestinal toxicity (RR = 0.44, 95%
CI = 0.29–0.68) and oral mucositis (RR = 0.33, 95% CI = 0.21–0.51).
SONG ET AL.
F I G U R E 2 Recommendation framework
involving the entire process of HDMTX
medication
3.1.2 | Is it necessary to test liver function before
HDMTX administration?
Recommendation 2
We recommend to routinely test liver function before administration,
and take it as one of the considerations for individualized dose
adjustment (strong recommendation, low-quality evidence). Remarks:
Liver function indicators include but are not limited to alanine
aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyl
transferase (GGT), alkaline phosphatase (ALP), and total bilirubin
(T-Bil).
2461
Rationale
HDMTX-induced hepatotoxicity mostly manifests as abnormal
laboratory indicators, and repeated administrations may cause
cumulative toxicity.35 Risk factors for hepatotoxicity include alcohol,
hepatitis virus infection and existing steatohepatitis.2 HDMTX should
be avoided or used with caution in patients with severe liver
dysfunction.
Evidence summary
There was no head-to-head study evaluating the clinical benefits of liver
function testing, and the systematic review (Supplementary Table S3)
2462
T A B L E 1 Referable dosing regimen for children and adolescents
with ALL or osteosarcoma based on baseline renal function
Corrected Ccr (mL/min) Dose adjustment
>100 100%
80–100 80%
60–80 70%
40–60 50%
20–40 40%
included only five studies comparing the changes in laboratory
indicators of liver function. After administration, the ALT value
(MD = 61.45, 95% CI = 57.88–65.03), the AST value (MD = 72.08,
95% CI = 67.36–76.80) and the GGT value (MD = 27.40, 95%
CI = 25.77–29.04) significantly increased, and the ALP value
(MD = 14.74, 95% CI = 24.66– 4.82) significantly decreased.
3.1.3 | Is it necessary to evaluate the pleural
effusion and ascites before HDMTX administration?
Recommendation 3
We suggest evaluating the pleural effusion and ascites. When large-
volume effusion is observed and HDMTX must be used, we suggest
reducing the dose, strengthening the therapeutic drug monitoring
(TDM), monitoring and dealing with adverse reactions in time (weak
recommendation, very low-quality evidence).
Rationale
Third-space compartments such as pleural effusion and ascites are
considered as potential relative contraindications to HDMTX therapy.
MTX may exit slowly from third-space accumulations, which results in
prolonged terminal plasma half-life, delayed excretion and serious
adverse events.36 Whether HDMTX should be used in such situations
depends on the balance of risks and benefits, but even more rigorous
2
monitoring is warranted if one proceeds.
Evidence summary
Two case reports37,38 were included in the systematic review.
37
Pauley reported that one ALL patient received HDMTX therapy and
was found to have pleural effusion and ascites. The MTX concentra-
tion first fell to the safe range (CDay9 < 0.1 μmol/L) and then
rebounded to CDay15 = 0.62 μmol/L. He developed acute renal failure
38
and bacteraemia, and died on day 18. Ding reported that a patient
with ascites received HDMTX therapy. He developed serious compli-
cations, and died of gastrointestinal bleeding on day 8, which was
considered to be related to ascites collection.
3.1.4 | Is it necessary to evaluate the combined
medication before MTX administration?
Recommendation 4
We recommend to fully evaluate comedications and use the following
drugs with caution. When these comedications are necessary, the
SONG ET AL.
MTX concentration and adverse reactions should be closely
monitored (strong recommendation, moderate quality evidence).
In terms of pharmacokinetics:
• drugs competing for plasma protein binding (such as aspirin,
phenytoin)
• drugs affecting MTX clearance (such as non-steroidal drugs,
penicillins, proton pump inhibitors, sulfonamides, ciprofloxacin)
• drugs affecting urine pH (such as vitamin C).
In terms of pharmacodynamics:
• drugs causing haematological toxicity, nephrotoxicity, liver toxicity,
and neurotoxicity
• warfarin, cyclosporine, hydrochlorothiazide and other drugs with
an adverse MTX interaction.
Evidence summary
A total of 11 studies were included in the systematic review.39
A supplementary search was performed of the Micromedex database
and the drug instructions. The evidence summary is provided in
Supplementary Table S4.
3.1.5 | Considering medication safety, is it
necessary to perform genetic testing before HDMTX
administration?
Recommendation 5
Genetic testing of MTHFR C677T (rs1801133) and A1298C
(rs1801131) can be considered for patients with haematological
malignancies (weak recommendation, moderate quality evidence).
Rationale
Methylenetetrahydrofolate reductase (MTHFR) is critical for folate
metabolism.6 Given this key role, genetic mutations might have signifi-
cant consequences for decreased enzyme activity and folate status, as
well as modulating the effects of antifolate drugs such as MTX.
Currently, MTHFR has been the most extensively studied gene in
pharmacogenetics studies of HDMTX, and the C677T SNP has
repeatedly been associated with increased HDMTX toxicity.6,7 The
survey of patient willingness showed that 86.90% of haematological
malignancy patients are willing to undergo genetic testing.29
Combining the evidence and patient preferences, the genetic test can
be considered and the dosage can be adjusted as appropriate.
Evidence summary
There was no head-to-head study evaluating the clinical benefits of
genetic testing, and related studies40–42 evaluated the impact of
genetic polymorphisms on clinical outcomes. A total of 44 studies
were included in the systematic review (Supplementary Table S5).
We found that the C677T mutation was associated with the
risk of haematological toxicity (TT vs CT/CC: OR = 1.85, 95%
SONG ET AL.
CI = 1.34–2.55), oral mucositis (TT/CT vs CC: OR = 1.51, 95%
CI = 1.18–1.92; TT vs CT/CC: OR = 1.61, 95% CI = 1.21–2.14; T vs
C: OR = 1.24, 95% CI = 1.01–1.51).
Recommendation 6
Genetic testing of ABCB1 C3435T (rs1045642) may be considered for
patients with haematological malignancies under certain conditions
(weak recommendation, low-quality evidence).
Rationale
The P-glycoprotein (P-gp) encoded by ABCB1/MDR1 is involved in the
efflux transport of MTX.6 We found that the C3435T SNP is related
to an increased risk of liver toxicity. The survey of patient willingness
survey showed that 86.9% of haematological malignancies patients
29
are willing to undergo genetic testing. Combining limited evidence
and patient preferences, the genetic testing can be considered for
specific conditions.
Evidence summary
There was no head-to-head study evaluating the clinical benefits of
genetic testing, and related studies43–45 evaluated the impact of
genetic polymorphisms on clinical outcomes. A total of nine studies
were included in the systematic review (Supplementary Table S6).
Significant associations were found with an increased risk of liver
toxicity (TT/CT vs CC: OR = 1.82, 95% CI = 1.11–2.97; TT vs
CT/CC: OR = 3.10, 95% CI = 1.46–6.57; T vs C: OR = 1.93, 95%
CI = 1.05–3.55).
Recommendation 7
Genetic testing of SLC19A1 A80G (rs1051266) is not recommended
for patients with haematological malignancies (weak recommendation,
low-quality evidence).
Rationale
The SLC19A1 (reduced folate carrier 1, RFC1) is responsible almost
exclusively for the active transport of MTX into all cell types.7
Although the reported results are far from consistent,6 our findings
support the lack of association with HDMTX toxicity.
Evidence summary
There was no head-to-head study evaluating the clinical benefits of
genetic testing, and related studies46–48 evaluated the impact of
genetic polymorphisms on clinical outcomes. A total of 16 studies
were included in the systematic review (Supplementary Table S7). We
found that there was no significant correlation between the A80G
mutation and the risk of haematological toxicity, nephrotoxicity, oral
mucositis and gastrointestinal toxicity (P ≥ .05).
Recommendation 8
Genetic testing is not recommended routinely for patients with
osteosarcoma, and it may be considered under certain conditions
(weak recommendation, low-quality evidence).
2463
Rationale
Limited evidence supports the association of MTHFR C677T with
HDMTX toxicity, while the impact of other genetic mutations still
remains ambiguous.49 The survey of patient willingness survey
showed that 82.5% of patients with osteosarcoma were willing to
undergo genetic testing.29 Combined with the clinical practice, the
clinical significance of genetic testing remains to be identified. Consid-
ering the limited evidence, clinical experience and economic costs,
genetic testing is not recommended routinely.
Evidence summary
A total of eight studies were included in the systematic review49
(Supplementary Table S8). In terms of MTHFR C677T, meta-analysis
of two studies showed that it was associated with the risk of severe
nephrotoxicity and (severe) oral mucositis. Regarding MTHFR
A1298C, no significant correlation was observed. Since few studies
have evaluated RFC1 A80G and ABCB1 C3435T, the correlation still
remains unclear.
3.2 | Routine dosing regimen
3.2.1 | How to hydrate and alkalize (including
timing and plan) when administering HDMTX?
Recommendation 9
We recommend to concomitantly employ intravenous hydration
(2.5–3 L/m2/day) and urinary alkalinization with sodium bicarbonate
at 12 h or earlier prior to initiation of HDMTX infusion. The
standardized hydration and urinary alkalinization should be employed
continuously before, during and after the administration (lasting 72 h
or more), until the MTX concentration is below 0.1–0.2 μmol/L (strong
recommendation, moderate quality evidence).
Rationale
Adequate hydration and urinary alkalization are necessary for
maintaining the solubility of MTX in renal tubules and MTX
clearance.50 Considering the gastrointestinal disorders induced by
chemotherapy and then the reduced absorption due to gastrointesti-
nal toxicity, combining the clinical feasibility, it is recommended to
add sodium bicarbonate to the hydration liquid to implement urinary
alkalization concomitantly.32 As for the implementation in clinical
practice, after estimating and recording the dietary fluid intake and
intravenous chemotherapy intake, the supplementary hydration liquid
should be administered to achieve the target hydration and urine pH,
which contains sodium chloride 0.9% injection, sodium bicarbonate
injection and/or potassium chloride injection. It is noted that monitor-
ing of fluid intake and output and attention to fluid balance contribute
to effective hydration with minimal risks.2
Evidence summary
A total of nine studies were included in the systematic review
(Supplementary Table S9). We found that adequate hydration and
2464
urinary alkalization 12 hours or earlier prior to initiation of HDMTX
infusion was associated with a decreased risk of nephrotoxicity
(RR = 0.46, 95% CI = 0.29–0.75). Continuous adequate hydration
and urinary alkalization were associated with improved patient
safety and shorter length of hospital stay. Concomitant hydration
and urinary alkalization during MTX infusion may reduce adverse
events.
3.2.2 | What is the target range of urine pH when
administering HDMTX?
Recommendation 10
We suggest maintaining urine pH at 7.0 or greater before and during
administration (weak recommendation, low-quality evidence).
Rationale
Precipitation of methotrexate crystals occurs in acidic urine,2 causing
acute kidney injury. Urine pH ≥ 7.0 can avoid drug precipitation and
promote renal excretion. In real clinical practice, we think it would be
better to measure the urine pH daily (before and during administra-
tion) if possible, until the plasma concentration of MTX reaches the
safe range.
Evidence summary
One cohort study was included in the systematic review
(Supplementary Table S10). We found that urine pH ≥ 7.0 can signifi-
cantly improve medication safety.51 In addition, the existing expert
consensus35,50 and clinical guidance34 consistently recommend to
maintain alkaline urine.
3.2.3 | What is the dosage regimen of HDMTX for
haematological malignancies?
Recommendation 11
For haematological malignancies, the dosage is commonly 1–8 g/m2,
and we suggest using the first dose combined with the maintenance
dose. The loading dose (1/10 of total dose) should be administered by
intravenous infusion over 0.5 h, while the remaining maintenance
dose (9/10) should be administered over 23.5 h. For primary central
nervous system lymphoma (PCNSL), MTX is commonly intravenously
infused over 3–4 hours (weak recommendation, expert opinion).
Rationale
For NHL or ALL, the first dose was infused quickly to achieve peak
plasma concentration, and the remaining dose was infused for a long
duration to maintain steady-state plasma concentration.35 For PCNSL,
the rapid infusion helps to achieve a higher diffusion of MTX across
the blood–brain barrier and increase the drug concentration in the
cerebrospinal fluid (CSF).52 Due to the lack of high-quality evidence, it
is necessary to fully evaluate patient's actual condition and previous
response to chemotherapy, and carefully formulate dosing and infu-
sion plans.
SONG ET AL.
Evidence summary
This recommendation referred to existing expert consensus and clini-
cal guidance.33,35,50
3.2.4 | What is the dosage regimen of HDMTX for
osteosarcoma?
Recommendation 12
For osteosarcoma, the dosage is commonly 8–12 g/m2, and we sug-
gest rapid infusion over 4–6 h (weak recommendation, expert
opinion).
Rationale
For patients with osteosarcoma, a higher concentration is required to
increase drug exposure to tumour tissue. Compared to the dosage
regimen of haematological malignancies, a higher dose is required and
infused over a shorter period of time.50 Due to the lack of high-quality
evidence, it is necessary to fully evaluate patient's actual condition
and previous response to chemotherapy, and carefully formulate
dosing and infusion plans.
Evidence summary
This recommendation referred to existing expert consensus and
clinical guidance.34,35,50,53
3.3 | Therapeutic drug monitoring (TDM)
3.3.1 | Is it necessary to implement TDM when
administering HDMTX?
Recommendation 13
We recommend implementing TDM routinely (strong recommenda-
tion, low-quality evidence).
Rationale
Patients' pharmacological response to MTX has long been known to
display great variability.6,8 The plasma concentration is affected by
many factors, and concurrent drugs are often more common in
patients with malignant tumours. Excessive concentrations may lead
to systemic toxic reactions. Implementing TDM and optimizing MTX
and leucovorin doses help to maintain the concentration in a safe and
effective target range. Among the interviewed patients, 95.24% of
patients with haematological malignancies were willing to undergo
TDM, and 92.50% of patients with osteosarcoma were willing.
Evidence summary
A total of four studies were included in the systematic review
(Supplementary Table S11). Conducting TDM and optimizing the MTX
dose helped to reach the target concentration range and reduce
adverse reactions. Moreover, the expert consensus,35,50 clinical
guidance33,34 and drug instructions53 consistently recommend to
implement TDM.
SONG ET AL.
3.3.2 | What method should be used to implement
TDM?
Recommendation 14
Considering the specificity and accuracy, we recommend to use liquid
chromatography-related analytical methods for TDM. When the con-
dition is limited or rapid testing is required, kit methods can be used
(strong recommendation, very low-quality evidence). Remark: Liquid
chromatography-related analytical methods include HPLC-MS/MS
and HPLC. Kit methods include FPIA, EMIT and CMIA.
Rationale
MTX exists in the body in the form of origins and metabolites,
including MTX, 7-OH MTX, polyglutamated MTX (PGMTX), and 2,4-
diamino-N10-methylmorphoic acid (DAMPA).54,55 Recently, PGMTX
and 7-OH MTX have been found to be associated with anti-
proliferative activity and adverse reactions.54,56–58 The HPLC and
HPLC-MS/MS methods can distinguish and detect both MTX and its
metabolites, but the cost is high and the sample processing is
complicated. Since TDM development varies significantly by region,
both liquid chromatography and kit methods play a role in TDM
implementation. The TDM method can be selected based on clinical
needs and feasibility, and the results of kit methods may need to be
corrected. It is noted that, after glucarpidase administration,
essentially all circulating MTX is converted into DAMPA and other
metabolites, and an immunoassay method may overestimate the
50
true MTX concentration. Therefore, the HPLC measurement is
recommended when using glucarpidase, while the FPIA measurement
should be avoided.
Evidence summary
We found no clinical study but only drug analytical studies.
A total of 10 studies were included in the systematic review
(Supplementary Table S12).59 The HPLC and HPLC-MS/MS methods
show advantages in specificity and sensitivity. The kit methods have
simple sample processing and short assay time, but the methods have
cross-reactivity with MTX and 7-OHMTX and the linear range is
narrow.35 Conclusions of comparisons between FPIA and EMIT
methods remain controversial. Comparisons of the above methods
are summarized in Supplementary Table S12.
3.3.3 | What is the timing of TDM during HDMTX
treatment?
Recommendation 15
For the 24 h infusion regimen, we recommend implementing TDM at
least 24 h (the end of infusion), 48 h and 72 h after the start of
HDMTX infusion, until the concentration is below 0.1–0.2 μmol/L.
When elimination delay, acute kidney injury or other serious adverse
reactions occur, the monitoring interval should be shortened and
the frequency should be increased (strong recommendation, expert
opinion).
2465
Recommendation 16
For the rapid infusion (less than 6 h) regimen, we recommend
implementing TDM at 3–6 h (the end of infusion), 24 h, 48 h and 72 h
after the start of HDMTX infusion, until the concentration is below
0.1–0.2 μmol/L. When elimination delay, acute kidney injury or other
serious adverse events occur, the monitoring interval should be short-
ened and the frequency should be increased (strong recommendation,
expert opinion).
Rationale
The TDM protocols can be grouped into two modes: For the 24 h
infusion regimen, C24h (the end of infusion) is considered to be the
steady-state concentration relating to efficacy and safety; while C48h
and C72h are mainly related to safety. For the rapid infusion (less than
6 h) regimen, C3–6h (the end of infusion) is considered to be the peak
concentration relating to efficacy and safety, while C24h, C48h and C72h
are mainly related to safety. The consensus on the safe range of MTX
concentration is below 0.1–0.2 μmol/L in most cases, and TDM can
be stopped once it is reached. It is worth mentioning that, for patients
with delayed MTX elimination and/or evidence of acute renal injury,
an MTX level less than 0.05 μmol/L can be considered as a stricter
safe range.
Evidence summary
The two recommendations referred to expert consensus, clinical
guidance and drug instructions.34,35,50,53
3.3.4 | What is the target range of C24h (the end of
infusion) for haematological malignancies?
Recommendation 17
We recommend the plasma concentration at the end of 24 h infusion
(C24h), or the steady-state plasma concentration (Css), be maintained at
16–40 μmol/L in ALL children (strong recommendation, moderate
quality evidence).
Rationale
For ALL children, C24h > 16 μmol/L may help to improve clinical
efficacy, and C24h > 40 μmol/L may increase the risk of toxicities.
Considering the balance between efficacy and safety, 16 μmol/L and
40 μmol/L are recommended as the lower and upper limits,
respectively. Adverse events should be closely monitored when
performing TDM.
Evidence summary
We found no clinical study for adult patients but only for ALL children.
A total of six studies were included in the systematic review
(Supplementary Table S13).60 C24h > 16 μmol/L was associated with
improved efficacy outcomes of complete response, haematological
response and 1.5-year recurrence rate.61 C24h > 40 μmol/L was
associated with an increased risk of liver toxicity, gastrointestinal
toxicity and oral mucositis.
2466
3.3.5 | What is the target range of C4–6h (the end of
infusion) for osteosarcoma?
Recommendation 18
We suggest that the plasma concentration at the end of 4–6 h infu-
sion (C4–6h), or the peak plasma concentration (Cmax), be maintained at
1000–1500 μmol/L (weak recommendation, low-quality evidence).
Rationale
HDMTX is commonly infused over 4–6 hours for patients with
osteosarcoma. C4–6h > 1000 μmol/L seems to contribute to improving
clinical efficacy. Efficacy improvement is not observed at C4-6h
> 1500 μmol/L, whereas it may cause serious adverse events.
Considering the balance between efficacy and safety, 1000 μmol/L
and 1500 μmol/L are suggested as the lower and upper limits,
respectively. Adverse events should be closely monitored when
performing TDM.
Evidence summary
A total of seven studies62–68 were included in the systematic review
(Supplementary Table S14).69 C4–6h > 1000 μmol/L was marginally
associated with better disease-free survival (DFS). C4–6h
> 1500 μmol/L was associated with an increased risk of serious
adverse events, and the lower ratio of 5-year event-free survival
(EFS).
3.3.6 | How to optimize the MTX dose according to
the TDM results?
Recommendation 19
We suggest that the MTX dose be optimized individually in
combination with pharmacokinetic properties, based on the TDM
results and target therapeutic concentration (weak recommendation,
very low-quality evidence).
Rationale
We suggest carefully adjusting the next dose based on the individual
conditions of patients, including chemotherapy response and TDM
results. For ALL children over 24 h infusion, if conditions permit, the
C24h can be estimated using a validated pharmacokinetic model after
the loading dose. According to the predicated C24h, the infusion rate
of the maintenance dose can be adjusted. 70
And finally, the total dose
in this cycle can be optimized.
Evidence summary
Most studies identified the influencing factors of pharmacokinetic
parameters, but the predictive model of individualized medication was
not established widely. A total of five studies were included in the
systematic review (Supplementary Table S15). The individualized
dose adjustment may avoid supratherapeutic concentrations in ALL
children.70 In children with ALL or osteosarcoma, individualized
prediction models for the next dose were established.71
SONG ET AL.
3.3.7 | For the rapid infusion (less than 6 h)
regimen, what is the target range of C24h after the start
of HDMTX infusion?
Recommendation 20
For the rapid infusion (less than 6 h) regimen, we suggest the plasma
concentration of 24 h (C24h) after the start of the infusion be
maintained below 10 μmol/L (C24h ≤ 10 μmol/L) (weak recommenda-
tion, low-quality evidence).
Rationale
The rapid infusion regimen is used for the treatment of osteosarcoma
and PCNSL. C24h is used to evaluate excretion delay and warn of
adverse events. C24h ≤ 10 μmol/L is widely regarded as normal
clearance and a decreased risk of adverse events. C24h > 50 μmol/L is
regarded as the critical value of early excretion delay.50,53 Supportive
care including hydration, urinary alkalization and leucovorin rescue
should be strengthened, and adverse events should be closely
monitored.
Evidence summary
One study was included in the systematic review
(Supplementary Table S16). C24h was associated with the time to
reach the target concentration, and all patients with C24h > 10 μmol/L
failed to meet the target safe range of C72h.72 This recommendation
also referred to the existing TDM protocol73 and clinical guidance.34
3.3.8 | What is the target range of C48h and C72h
after the start of HDMTX infusion?
Recommendation 21
We recommend the plasma concentration of 48 h (C48h) and 72 h
(C72h) after the start of the infusion be maintained below 1 μmol/L
and below 0.1–0.2 μmol/L, respectively. When C72h > 0.1–0.2 μmol/L,
shortening the monitoring interval and increasing the frequency can
be considered. TDM should be implemented until the concentration
reaches the safe range (strong recommendation, moderate quality
evidence).
Rationale
C48h ≤ 1 μmol/L is commonly regarded as normal clearance and a
decreased risk of adverse events, and C48h > 5 μmol/L is regarded as
delayed early excretion.50,53 C72h is widely used to determine whether
the safety range has been reached. C72h ≤ 0.1–0.2 μmol/L is regarded
as the safe range,34,50,53 which is the indication for stopping TDM and
rescue.
Evidence summary
A total of eight studies were included in the systematic review of C48h
target range (Supplementary Table S17). Compared with C48h
< 1 μmol/L, C48h > 1 μmol/L is associated with an increased risk
of haematological toxicity, liver toxicity, gastrointestinal toxicity
SONG ET AL. 2467

and other adverse events. A total of four studies were included Rationale
in the systematic review of the C72h target range Under the premise of no difference in medication safety, in theory,
(Supplementary Table S18). Compared with C72h < 0.1 μmol/L, C72h the lower the leucovorin dose, the weaker the antagonistic effect on
> 0.1 μmol/L is associated with an increased risk of oral mucositis chemotherapy. The clinical benefit of shortening the dosing interval
and skin toxicity. was not observed.35 So the recommended dose is 10–15 mg/m2
q6h.33,35 Considering the gastrointestinal disorder induced by chemo-
therapy and the decreased bioavailability of high-dose leucovorin, IV
3.4 | Leucovorin rescue or IM injection are recommended while oral administration should be
avoided.35
3.4.1 | When should leucovorin be administered?
Evidence summary
Recommendation 22 A total of four studies comparing leucovorin doses were included in
For the 24 h infusion regimen, we recommend administering the first the systematic review (Supplementary Table S20). Compared with
dose of leucovorin at 36–44 h after the start of HDMTX infusion. doses of 20 or 30 mg/m2, there was no difference in safety outcomes
When serious adverse reactions occur, the timing of the first dose of haematological toxicity, liver toxicity and gastrointestinal toxicity in
should be adjusted individually (strong recommendation, low-quality the 15 mg/m2 dose.
evidence).

Recommendation 23 3.4.3 | How to optimize the dose of leucovorin

For the rapid infusion (less than 6 h) regimen, we suggest administer-
ing the first dose of leucovorin at 12–24 h after the start of HDMTX
infusion. When serious adverse reactions occur, the timing of the first
dose should be adjusted individually (weak recommendation, expert
opinion).
Rationale
Excessive early rescue may antagonize the effect of chemotherapy,
whereas serious adverse events may occur if the timing of rescue is
late. For patients with haematological malignancies treated with a
24 h infusion regimen, delaying rescue to 42 h or 44 h has been
proven to be safe and effective. For patients with osteosarcoma
or PCNSL, the timing should be adjusted individually based on the
clinical situation.
Evidence summary
A total of eight studies were included in the systematic review for
haematological malignancies (Supplementary Table S19). Compared
with rescue at 36 h, delayed rescue (42 h or 44 h) did not increase the
risk of haematological toxicity, liver toxicity and nephrotoxicity. No
difference was observed in the efficacy outcomes of the CR rate and
recurrence rate. The recommendation for patients with osteosarcoma
based on the TDM results?
Recommendation 25
We suggest optimizing the dose of leucovorin based on the plasma
concentration of MTX at 42 h–48 h (C42–48h), as shown in Table 2
(weak recommendation, expert opinion).
Rationale
This recommendation referred to the existing clinical guidance of ALL
children.33 The leucovorin should be administered until the MTX con-
centration is below 0.1–0.2 μmol/L. When using calcium folinate,
close attention should be paid to the side effects of hypercalcaemia.
When the single dose is higher, it should be infused over an hour.33
As for the dose adjustment for calcium folinate in patients with OS at
24 h, the regimen in the randomized trial protocol of the European
and American Osteosarcoma Study (EURAMOS) Group should be
referred to after evaluation.74
TABLE 2 Leucovorin dosage regimen

or PCNSL referred to the existing expert consensus35,50 and clinical C42–48h of MTXa (μmol/L) Leucovorin
34
guidance. ≤0.1–0.2 Commonly unnecessary
0.2–1.0 15 mg/m2, q6hb
1.0–2.0 30 mg/m2, q6h
3.4.2 | What is the dosage regimen of leucovorin?
2.0–3.0 45 mg/m2, q6h
(the initial dose, route of administration and frequency)
3.0–4.0 60 mg/m2, q6h
4.0–5.0 75 mg/m2, q6h
Recommendation 24
>5.0 C42–48h  weight (kg), q6h
In the first dose, we commonly recommend administering leucovorin
15 mg/m2, q6h, intravenous (IV) or intramuscular (IM) injection (strong a
C42–48h of MTX: the plasma concentration of MTX at 42–48 h.
b
recommendation, low-quality evidence). q6h: administered every 6 hours.
2468
3.5 | Management of toxicities
3.5.1 | Is it necessary to monitor liver and kidney
function after HDMTX administration?
Recommendation 26
We suggest paying attention to testing liver and kidney function after
administration until the plasma concentration reaches the safe range
(weak recommendation, low-quality evidence).
Rationale
Liver and kidney function damage are common adverse reactions
to HDMTX, and significant changes in laboratory test values of liver
and kidney function have been observed. Although the C7-OH-MTX
is found to be potentially useful in predicting renal or liver injury,57,75
CMTX < 0.1–0.2 μmol/L is currently still widely used as the safe range.
Evidence summary
A total of seven studies comparing the renal function changes were
included in the systematic review (Supplementary Table S21). After
administration, the value of Ccr (MD = 10.22, 95% CI = 13.87–
6.57) significantly decreased, and the value of cystatin C (CysC)
(MD = 0.34, 95% CI = 0.29–0.38) significantly increased. A total of
four studies comparing the liver function changes were included in
the systematic review (Supplementary Table S2).
3.5.2 | How to strengthen supportive care when an
adverse reaction occurs? (hydration, urine alkalization
and leucovorin rescue)
Recommendation 27
When an adverse reaction occurs, we suggest increasing leucovorin
dose, strengthening personalized hydration, continuously alkalizing
the urine to maintain the urine pH above 7.0, and giving other symp-
tomatic treatments such as gargling in time (weak recommendation,
expert opinion).
Rationale
This recommendation is based on expert consensus. When strength-
ening supportive care, it is necessary to fully consider the individual
situation of the patient, such as heart failure and renal insufficiency.
And close attention should be paid to monitoring blood electrolytes.
Concerning the gargles for the treatment of oral mucositis, chlorhexi-
dine, metronidazole, vitamin B complex, lidocaine and leucovorin can
be considered as components of the gargles.
3.5.3 | When should blood purification be
considered?
Recommendation 28
When excessively high plasma concentrations, severe acute kidney
injury or other serious adverse reactions occur, and conventional
supportive care cannot effectively reduce the plasma concentration
SONG ET AL.
in the short term, blood purification can be considered. We
suggest using high-flux haemodialysis (HFHD), combined blood
purification and continuous renal replacement therapy (CRRT), and
paying attention to monitoring the concentration rebound and side
effects of blood purification (weak recommendation, low-quality
evidence).
Rationale
When the blood concentration is excessive, the intracellular rescue
effect may be inhibited, and blood purification can be considered to
achieve extracellular rescue. When the concentration is extremely
high, a combination of HFHD and haemoperfusion is recommended.76
When there is haemodynamic instability or life-threatening
emergencies, CRRT is suggested.77 Moreover, glucarpidase, an
approved drug for toxic MTX concentrations, can be considered as
a treatment option, and recommendations regarding glucarpidase
administration have been provided in a previous consensus
guideline.50
Evidence summary
The relevant evidence is mostly case reports, and one cohort study
was included in the systematic review (Supplementary Table S22).
A combination of HFHD and haemoperfusion significantly improved
renal function, and shortened the length of hospital stay. The
comparisons of different blood purification technologies are summa-
rized in Supplementary Table S23.78,79
4 | DI SCU SSION
4.1 | Summary of recommendations
Overall, the evidence-based guideline formulated 28 recommendations
for HDMTX medication based on evidence from systematic reviews.
In the GRADE system, randomized controlled trials (RCTs) begin as
high quality, while observational studies begin as low quality.80 Due
to the properties of clinical questions in this guideline, observational
studies are best suited for answering most of the questions
when RCTs are not feasible, which has led to five moderate quality,
13 low-quality and three very low-quality batches of evidence.
Despite the seemingly general level of evidence, 12 strong recom-
mendations have been formulated. The strength of recommendations
depends on the balance of benefits and harms, patients' values and
preferences, and resources and cost, apart from the quality of
evidence.27,28,30,81
4.2 | Comparison with existing consensus
To the best of our knowledge, this is the first evidence-based guide-
line covering the whole process of HDMTX administration. In 2019,
the Chinese Society of Clinical Oncology released an expert consen-
sus for HDMTX therapy with leucovorin rescue,35 which focused on
SONG ET AL.
the protocol of leucovorin rescue and strategies for preventing and
managing toxicities. In 2018, a consensus guideline for the use of
50
glucarpidase was published, which provided recommendations to
identify the population of patients who would benefit from
glucarpidase. Compared with the existing expert consensus, the main
strengths and differences of our guideline are as follows. First, we
followed the internationally recognized methodology of guideline
development. For example, we performed a systematic review for
each clinical question, used the GRADE approach and Delphi vote to
formulate recommendations, conducted external peer review, and
reported the guideline according to the RIGHT statement. Second, we
emphasized the management of conflicts of interest and involved
patients in guideline development by conducting an investigation of
patients' values and preferences, which enhances the transparency
and patient acceptance of our guideline. Third, our guideline provides
practical recommendation regarding the whole process of HDMTX
administration, including evaluation prior to administration, dosing
regimen, genetic testing, TDM, standardized supportive care and
management of toxicities.
4.3 | Gaps in knowledge
The development of the guideline reflects the gap between current
research and practice. Considering the cost of genetic testing, well-
designed studies evaluating the direct clinical benefit are still needed
to support routine genetic testing. With respect to TDM, the target
range of C24h for adult patients with haematological malignancies still
remains unclear. Due to the complex properties of HDMTX, patients
are very likely to benefit from individualized dosage adjustment, but
the predictive model of individualized medication has not been
established widely. Economic studies are needed to evaluate the
benefits of genetic testing and frequent TDM as well. In addition,
although systematic reviews were performed for each clinical
question, the evidence was insufficient to answer some questions.
Thus, we formulated recommendations for the aforementioned
questions based on wide clinical experience and relevant clinical
guidance,82 such as the dosage regimens (recommendations
11 and 12) and TDM timing of HDMTX (recommendations 15 and
16). Therefore, further high-quality studies are needed in the above
fields.
5 | C O N CL U S I O N
In conclusion, we developed an evidence-based practice guideline
with respect to HDMTX medication using a rigorous and
multidisciplinary approach. This guideline provides comprehensive
and practical recommendations involving the whole process of
HDMTX administration to health care providers. Implementation and
assessment of guideline-concordant rates and impacts are important
future steps.
2469
AC KNOW LEDG EME NT S
We sincerely thank all pharmacists and students who proposed
comments for the draft of clinical questions (Zhanmiao Yi, Wei Liu,
Ken Chen) and participated in searching, screening and summarizing
of clinical evidence (Yi Ma, Xiaoqing Ren, Zheng Li, Enyao Zhang,
Jieyu Zhao). We thank all members of the guideline development
groups for their valuable contribution, especially all the external
reviewers who proposed comments for the draft guideline.
This work was supported by the National Natural Science
Foundation of China (NSFC) (grant number 72074005), and the
Division of Therapeutic Drug Monitoring, Chinese Pharmacological
Society.
COMPETING INTER ESTS
Members of the guideline steering committee, guideline consensus
panel, and evidence synthesis team completed a declaration of
conflicting interests form before attending guideline meetings. All
authors reported no potential conflicts of interest.
CONT RIB UTOR S
All authors are core members of guideline working groups, and were
involved in the guideline development and the manuscript. (I) RS
Zhao, ZW Song: Conception and design, management and organiza-
tion of the guideline development. (II) RS Zhao: PI for this paper.
(II) ZW Song: responsible for the evidence synthesis, and writing the
first draft of the manuscript. (III) ZW Song, Y Hu, S Liu, GR Wang,
D Jiang, ZC Huang, ZY Tan, QN Lin (evidence synthesis team):
collecting clinical questions, retrieval, evaluation, synthesis and
grading of evidence, conducting systematic reviews, and formulating
the summary of finding tables and the recommendation decision
tables. (IV) SD Zhai, XL Zhang, YP Ling, GH Du, YK Shi (steering
committee): making final decisions at each stage, and controlling
throughout the entire process. (V) YL Chen, M Dong, RC Guo, W
Guo, HB Huang, XJ Huang, HM Jing, XY Ke, GH Li, LY Miao, XH
Niu, F Qiu, JN Shen, JY Tang, TY Wang, XL Wang, Z Wang, JH Wu,
SY Zhan, BK Zhang, LL Zhang, YH Zhang, LM Zhao, JC Zhen,
HY Zheng, Z Zhu (consensus panel): determining the clinical
questions, voting for recommendations, and building consensus.
(VI) W Zhang, LB Zhao (external review group): responsible for the
external review, reviewing and proposing comments for the draft
guideline. (VII) All authors: critical revision and approval of the final
manuscript.
DATA AVAILABILITY STAT EMEN T
The data that support the findings of this study are available from the
corresponding author upon reasonable request. Some data may not
be made available because of privacy or ethical restrictions.
OR CID
Suodi Zhai https://orcid.org/0000-0003-2220-359X
Xiaoling Wang https://orcid.org/0000-0003-2136-7410
Rongsheng Zhao https://orcid.org/0000-0002-3266-3496
2470
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How to cite this article: Song Z, Hu Y, Liu S, et al. Medication
therapy of high-dose methotrexate: An evidence-based
practice guideline of the Division of Therapeutic Drug
Monitoring, Chinese Pharmacological Society. Br J Clin
Pharmacol. 2022;88(5):2456-2472. doi:10.1111/bcp.15134