Skip to main content

High-dose methotrexate in ICU patients: a retrospective study

Abstract

Background

High-dose methotrexate (HD-MTX) is commonly used in the treatment of solid tumors and hematological malignancies. Severe toxicities are frequent, leading to organ dysfunction and death. Risk–benefit ratio of using HD-MTX in critically ill patients is unknown. This study aims to describe MTX-induced toxicities and to assess outcome in ICU patients. We conducted a retrospective single-center study conducted in a university hospital ICU between January 2002 and December 2018. Consecutive patients treated by HD-MTX were included.

Results

33 patients (24 men and 9 women) aged 48 years [34–63], were included. B cell lymphoma had been diagnosed in 31 patients (Burkitt, n = 14; diffuse large B-cell lymphoma with CNS (central nervous system) involvement, n = 9; primary CNS lymphoma, n = 5) and T-cell lymphoma in two patients. Patients were mainly admitted for coma (n = 14; 42%) or acute kidney injury (n = 8; 24%). MTX was administered at a median dose of 6.1 g [5–14]. Fourteen patients had concomitant medication interacting with MTX. Median MTX clearance was 4 days [4–5]. Frequent MTX-related complication were mucositis (n = 21, 64%), diarrhea (n = 14, 44%) or hepatic failure (n = 15, 45%). During ICU stay, 11 patients experienced acute kidney injury (KDIGO stage 3 [2–3]). Two patients received carboxypeptidase and three underwent dialysis. Overall, 19 patients (57%) required mechanical ventilation, 10 (30%) vasopressors. Hospital mortality was 30% (n = 10). Cox model identified MTX concentration 24 h after administration higher than 4.6 µmol/L as associated with hospital mortality (HR 6.7; 95% CI 1.6–27.3).

Conclusions

To our knowledge, this is the first study assessing characteristics and outcome of critically ill patients receiving HD-MTX. MTX concentration at H24 was associated with hospital mortality. Despite underlying malignancy, ICU support of these patients was associated with a meaningful survival.

Background

Intravenous high-dose methotrexate (HD-MTX) is commonly used in the treatment of hematological malignancies, particularly in high-grade lymphomas [1]. MTX-related toxicities are common, leading to organ dysfunction that can be very severe, and rarely to death [1]. Acute kidney injury (AKI) is frequently reported, affecting up to 35% of adult patients, mostly in relation with intratubular crystal formation or endothelial injuries [1, 2].

This drug requires a close monitoring and management of MTX-related toxicities relies mostly on preventing measures [1, 3]. AKI is frequent in critically ill patients with newly diagnosed high-grade hematological malignancies [4] and is associated with a high level of frailty. Whether ICU patients may be considered eligible for HD-MTX and risk–benefit ratio in this setting has never been assessed.

This primary objective of this study was to assess outcome in critically ill patients requiring HD-MTX infusion. Secondary objectives were to describe toxicities and risk factors of poor outcome in this setting.

Methods

Patients and data collection

We retrospectively reviewed the medical charts of all consecutive adult patients admitted to the intensive care unit of one university hospital from January, 1st, 2002 to December 31th, 2018, and who received HD-MTX for hematological malignancy or solid tumor. There were no exclusion criteria.

HD-MTX was defined by a single intravenous infusion greater than 500 mg/m2. The different stages of toxicity were defined according to the CTCAE [5]. MTX complete elimination was considered when MTX concentration was lower than 0.1 µmol/L.

This study was approved by a local ethic committee (Société de Réanimation de Langue Française, CE SRLF 19-01). According to French law, need for informed consent was waived.

Statistical analysis

Results are described as medians and interquartile ranges (IQR) for quantitative variables and numbers and percentages for qualitative variables. We used a non-parametric Wilcoxon tests and Fisher exact tests for baseline univariate comparisons between two groups.

Cox regression model were performed to identify factors associated with hospital mortality. Variable selection was performed on a stepwise fashion, backward conditional model according to P value with entry P value of 0.2 and critical removal P value of 0.1. Proportional hazard assumption was checked in the final model.

All tests were two-sided, and P values less than 0.05 were considered significant. Analyses were done using R software version 4.3.4 (R Project for Statistical Computing, Wien, Austria) and with ‘Survival’ packages.

Results

33 patients (24 men, 9 women) were included with a median age of 48 years [34–63]. All the patients had aggressive hematological malignancies and most of them (n = 31/33) had not received any antitumor treatment. B-cell lymphoma had been diagnosed in 31 patients (Burkitt [n = 14]; diffuse large B-cell lymphoma with CNS involvement [n = 9]; primary CNS lymphoma [n = 5]; primary effusion lymphoma [n = 2]; intravascular lymphoma [n = 1]) and T-cell lymphoma in two patients. Twelve (36%) had HIV infection, three had hypertension and one patient was diabetic (Table 1).

Table 1 Characteristics of patients at study inclusion

Patients were mainly admitted to the ICU for coma (n = 14; 42%) or acute kidney injury (n = 8; 24%). Five (15%) patients presented respiratory failure and only one patient had shock. Fifteen patients had a Glasgow Coma Scale of 12 or below and all except one presented with neurologic involvement related to lymphoma. SOFA score was 4 [1–5] at admission and 2 [1–5] the day of MTX infusion. All the patients except one presented a normal renal function at baseline (median serum creatinine = 55 µmol/L [41–74]), 12 experienced AKI episode in the last 3 months, including 8 requiring renal replacement therapy (RRT) (Table 1).

MTX was administered at a median dose of 3.4 g/m2 [2.6–7.4] and the median delay between ICU admission and MTX infusion was 4 days [2–7]. Twenty patients (61%) received concomitant intrathecal MTX. Other most commonly used chemotherapy drugs were cyclophosphamide (n = 23), doxorubicin (n = 23) and vincristine (n = 21). Median body mass index (BMI) was 24.9 [21.4–27.1] and median albumin level was 33 g/L [26–37]. Median creatinine level was 55 µmol/L [41–74] on the day of MTX administration. All patients received parenteral hyperhydration and alkalinization. Only 6 patients failed to achieve urine pH above 7.5 at least once within the first 24 h following MTX infusion. Folinic acid rescue was started 24 h after MTX infusion for all patients except one. The median time required until a complete elimination of MTX was 4 days [4–5]. Fourteen patients had concomitant medication interacting with MTX, mostly piperacillin–tazobactam (n = 8), proton-pump inhibitors (n = 9) or levetiracetam (n = 4). Seven patients presented serous effusions that required fluid removal (pleural effusions, n = 6 and ascites, n = 1).

More than 80% of patients (n = 27) experienced at least one MTX-related toxicity (Table 2). The most frequent MTX-related complications were mucositis (n = 21, 64%; median CTCAE grade 3 [2–4]), diarrhea (n = 14, 44%; median CTCAE grade 2 [2–3]) or liver tests disturbance (n = 15, 45%; median CTCAE grade 3 [2–4]). Following MTX infusion, the majority of patients developed neutropenia (n = 26) and acquired bacterial infections (n = 17, 51%). During ICU stay, one-third of patients (n = 11) experienced acute kidney injury (KDIGO stage 2.5 [2–3]) and median onset was reached 3.5 days [2–5] after MTX infusion. Eight patients also received concomitant nephrotoxic agents including contrast media (n = 3) and aminoglycosides (n = 3). Renal toxicity and MTX overdosage lead to carboxypeptidase G2 administration in 2 patients and need for RRT initiation in three.

Table 2 MTX-related toxicities and outcome

Overall, 19 patients (57%) required mechanical ventilation, within a median time of 5 [1–12] days prior to MTX administration, and 10 (30%) vasopressors. Median length of ICU stay was 11 days [6–24]. Overall, ICU and hospital mortality were 18% (n = 6) and 30% (n = 10), respectively. Eighteen patients (55%) were alive 6 months after ICU discharge among whom, 15 (83%) had a complete and sustained hematological remission.

In univariate analysis, mortality was associated with older age (median age 63.5 years [51.25–68.75] vs 38 years [31–51.5, p = 0.013]), lower albumin level (27.5 g/L [24–31.75] vs 36 g/L [31–38], p = 0.045), and higher severity as assessed by SOFA score (6 [4.25–9] vs 2 [1–5], p = 0.022).

After adjustment for patients’ severity, MTX concentration 24 h after administration was independently associated with hospital mortality (HR if concentration above 4.6 μmol/L 6.7; 95% CI 1.6–27.3) (Table 3) (Fig. 1). In non-survivors, creatinine levels were significantly higher the day after MTX administration (p = 0.0017) and during the first week (p = 0.026) (Fig. 2).

Table 3 Variables associated with hospital mortality after adjustment
Fig. 1
figure1

Adjusted influence of MTX dosage at H24

Fig. 2
figure2

Relationship between creatinine and hospital mortality within the first week after MTX infusion

Discussion

To our knowledge, this is the first study assessing benefits and risk of HD-MTX in critically ill patients. This study underlines the high rate of risk factors for HD-MTX toxicity and the high rate of MTX-related toxicities. Our results also underline that 6-month survival may be obtained in 55% of the patients and that complete remission may be obtained in 83% of them.

In the literature, classically 2 to 12% of non-ICU patients are reported to develop renal failure following HD-MTX. In fact up to 35% of patients experienced AKI, with a large heterogeneity according to the studied population, HD-MTX protocols and AKI criteria [6]. In critically ill patients, AKI incidence also varies widely from 22 to 67%, discrepancies mainly relying on the definition applied [7]. In our study, we found a high rate of AKI as one in three patients experienced renal failure. This is in line with a previous study in which the authors showed that two-thirds of critically ill patients with newly diagnosed aggressive hematological malignancies developed AKI [4]. Our results highlight that MTX-induced renal toxicity is very frequent in ICU patients.

Survival of patients with hematological malignancies has improved over the past decades and an increasing number of patients may need ICU admission [8]. In previous studies in cancer patients receiving chemotherapy in the intensive care unit, hospital mortality is reported around 40% [9]. Our study, concurrently suggests the feasibility of HD-MTX in this setting, demonstrating that despite the high toxicity rate, a 6-month survival rate of 55% may be achieved, the majority of survivors achieving complete remission.

Dose–toxicity relationship of MTX has been descried previously. The most commonly used threshold is a concentration greater than 10 µmol/L 24 h after MTX infusion or greater than 1 µmol/L at H48 [3]. Evans et al. [10] previously demonstrated that values above 10 µmol/L 24 h after the start of MTX infusion were associated with an increased risk of toxicity. As no published data exist in ICU patients, optimal early MTX concentrations predicting the outcome remain unknown.

This study suffers however several limitations. First, due to its retrospective design, exhaustivity of data was limited. Thus, exact assessment of optimal MTX concentration predicting poor outcome could not be assessed. Second, the small sample size led to limited statistical power, negative findings needing to be interpreted cautiously. Moreover, patients deemed eligible to HD-MTX infusion were likely to be selected according to performance status and clinical severity. Despite these limits, our study demonstrates feasibility of HD-MTX with meaningful chances of long-term survival and complete remission.

Conclusion

This study demonstrates feasibility of HD-MTX in a selected group of critically ill cancer patients. Although the toxicity rate was high, long-term survival was achieved in more than half of the patients and complete remission was achieved in most of these later. Additional studies are needed to allow better identification of patients at high risk of toxicity.

Availability of data and materials

The dataset supporting the conclusions of this article is included within the article (and its Additional files 1, 2, and 3).

Abbreviations

AKI:

Acute kidney injury

BMI:

Body mass index

CNS:

Central nervous system

CTCAE:

Common Terminology Criteria for Adverse Events

HD-MTX:

High-dose methotrexate

ICU:

Intensive care unit

MTX:

Methotrexate

SOFA:

Score, sepsis-related organ failure assessment

References

  1. 1.

    Howard SC, McCormick J, Pui C-H, Buddington RK, Harvey RD. Preventing and managing toxicities of high-dose methotrexate. Oncologist. 2016;21(12):1471–82.

    CAS  Article  Google Scholar 

  2. 2.

    Garneau AP, Riopel J, Isenring P. Acute methotrexate-induced crystal nephropathy. N Engl J Med. 2015;373(27):2691–3.

    Article  Google Scholar 

  3. 3.

    Widemann BC, Adamson PC. Understanding and managing methotrexate nephrotoxicity. Oncologist. 2006;11(6):694–703.

    CAS  Article  Google Scholar 

  4. 4.

    Canet E, Zafrani L, Lambert J, Thieblemont C, Galicier L, Schnell D, et al. Acute kidney injury in patients with newly diagnosed high-grade hematological malignancies: impact on remission and survival. PLoS ONE. 2013;8(2):e55870.

    CAS  Article  Google Scholar 

  5. 5.

    Common Terminology Criteria for Adverse Events (CTCAE) | Protocol Development | CTEP [Internet]. https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. Accessed 8 Oct 2019.

  6. 6.

    Jahnke K, Korfel A, Martus P, Weller M, Herrlinger U, Schmittel A, et al. High-dose methotrexate toxicity in elderly patients with primary central nervous system lymphoma. Ann Oncol Off J Eur Soc Med Oncol. 2005;16(3):445–9.

    CAS  Article  Google Scholar 

  7. 7.

    Schetz M, Darmon M. Measuring acute kidney injury around the world: are we using the right thermometer (and adequately)? Intensive Care Med. 2015;41(10):1857–9.

    Article  Google Scholar 

  8. 8.

    Darmon M, Bourmaud A, Georges Q, Soares M, Jeon K, Oeyen S, et al. Changes in critically ill cancer patients’ short-term outcome over the last decades: results of systematic review with meta-analysis on individual data. Intensive Care Med. 2019;45(7):977–87.

    Article  Google Scholar 

  9. 9.

    Darmon M, Thiery G, Ciroldi M, de Miranda S, Galicier L, Raffoux E, et al. Intensive care in patients with newly diagnosed malignancies and a need for cancer chemotherapy. Crit Care Med. 2005;33(11):2488–93.

    Article  Google Scholar 

  10. 10.

    Evans WE, Pratt CB, Taylor RH, Barker LF, Crom WR. Pharmacokinetic monitoring of high-dose methotrexate. Early recognition of high-risk patients. Cancer Chemother Pharmacol. 1979;3(3):161–6.

    CAS  Article  Google Scholar 

Download references

Acknowledgements

None.

Funding

No part of the work presented has received financial support from any source.

Author information

Affiliations

Authors

Contributions

MD is the guarantor for the content of the manuscript, including the data and analysis. SV, EM, EA, MD contributed substantially to the study design, data analysis and interpretation, and the writing of the manuscript. SV, REM, EA, MD contributed substantially to patients recruitment, collecting data and manuscript revision. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Sandrine Valade.

Ethics declarations

Ethics approval and consent to participate

This study was approved by a local ethic committee (commission d’éthique de la Société de Réanimation de Langue Française, CE 19-01). At ICU admission, patients and relatives receive a leaflet informing them of the existence of clinical studies in the ward and the collection of data with the possibility of declining the use of these data.

Consent for publication

Not applicable

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Valade, S., Mariotte, E., Azoulay, E. et al. High-dose methotrexate in ICU patients: a retrospective study. Ann. Intensive Care 10, 81 (2020). https://doi.org/10.1186/s13613-020-00693-5

Download citation

Keywords

  • Methotrexate
  • Acute kidney injury
  • Outcome
  • Hematological malignancies
  • Drug-related side effects
  • Antineoplastic agents