Optimal Management of Methotrexate Intoxication in a Child

with Osteosarcoma
Hlne Peyriere, Marylne Cociglio, Genevive Margueritte, Catherine Vallat, Jean-Pierre Blayac, and
Dominique Hillaire-Buys

OBJECTIVE: To describe the time course and management of methotrexate (MTX) toxicity in a 14-year-old Hispanic boy with
osteosarcoma treated with high-dose MTX.
CASE SUMMARY:

During the sixth cycle of high-dose MTX, severe intoxication was observed with high MTX plasma concentrations,
acute renal failure, and hepatitis, followed by mucositis and moderate myelosuppression. Intensification of urine alkalinization and
increased leucovorin dosages did not decrease plasma concentrations of MTX or prevent systemic toxicities. Carboxypeptidase G2
and aminophylline were thus administered as a second-intention rescue strategy. Within 2 weeks, a recovery of clinical symptoms
and normalization of the biological abnormalities were observed. Limb salvage surgery was performed, which permitted classifying
the patient as an MTX high-responder. Thereafter, MTX was successfully resumed, leading to clinical recovery of the patient.
Concomitantly, homocysteine plasma levels, a marker of the pharmacodynamic effect of MTX, were measured. During the
intoxication, homocysteine plasma levels were significantly increased, parallel to the excessive MTX plasma concentrations
observed.

DISCUSSION:

According to the excessive MTX levels measured in this patient, along with the observed clinical (mucositis) and
biological (hepatitis, renal injury) adverse effects, we suggest that MTX may be a cause of these complications. Use of the Naranjo
probability scale indicated a probable relationship between the complications and MTX.

CONCLUSIONS: This observation shows that severe complications observed during one cycle of high-dose MTX is not predictive of
the tolerability of further courses. Optimal management of such complications, using specific therapeutic intervention, may be
considered.
KEY WORDS: child, methotrexate, osteosarcoma.

Ann Pharmacother 2004;38:422-7.

Published Online, 23 Jan 2004, www.theannals.com, DOI 10.1345/aph.1D237

ince the first trial using high-dose methotrexate (MTX)

S
(>1 g/m ) as adjuvant chemotherapy in the treatment
of osteosarcoma in children, the survival rate of these pa2

tients has gradually improved.1 Urine alkalinization, vigorous hydration, and rescue with leucovorin are used to minimize the toxicities associated with this drug.2 Monitoring
of MTX is needed to detect elevated plasma concentrations and identify children at risk for acute toxicity. By incorporating these measures, the incidence of life-threatening toxicity has been lowered from 10% to <1%.2,3
In cases of delayed MTX elimination, a decrease in
MTX clearance leads to higher plasma concentrations and

Author information provided at the end of the text.

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The Annals of Pharmacotherapy

a marked enhancement of other toxic effects associated

with the drug. In such situations, intensification of alkaline
diuresis and increased leucovorin dosage are not always
enough to prevent toxicity. Both hemodialysis and hemoperfusion are ineffective in removing significant quantities
of MTX.2 Consequently, 2 main therapeutic strategies have
been proposed to decrease the risk of severe complications
in such cases. In the first of these, carboxypeptidase G2
(CPDG2) is used to rapidly hydrolyze MTX to nonactive
and nontoxic metabolites.4 In the second of these strategies, aminophylline has been successfully administered to
patients with acute neurotoxicity related to MTX.5
A marker of the pharmacodynamic effect of MTX as an
antifolate drug is the estimation of plasma homocysteine
levels. In patients with cancer receiving high-dose MTX,

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there is a rapid increase in plasma homocysteine in less

than a few hours after MTX administration.6-8
We report a well-managed observation of MTX intoxication in a child treated for osteosarcoma. Despite severe
complications during one cycle, MTX therapy was successfully continued in subsequent cycles.

(Figure 1). The patient showed acute renal failure and cytolytic hepatitis
at this time. Renal echography showed an increase in the volume of kidney and hyperechogenic kidney without obstructive syndrome. At that
time, the dosage of leucovorin was increased to 35 mg/m2 every 6 hours,
alkaline hydration was continued, and furosemide was administered.
Aminophylline 0.5 mg/kg/h was then started. Four days later, the serum
creatinine level, blood urea, uric acid, and MTX plasma concentrations
still showed abnormal values. Creatinine clearance calculated with the
Schwartz formula was 10 mL/min.10 The following day, CPDG2 (50
units/kg) was administered. After the injection, MTX plasma concentrations decreased from 614 to 24.1 mol/L within 16 hours.
Five days after MTX infusion, renal failure was still severe, despite
administration of furosemide and aminophylline. Alkaline hydration
consisted of bicarbonates 2.5l mg/24 hours, saline solution 750 mg/24
hours, and 5% glucose solution 750 mg/24 hours. Using these procedures, urinary pH remained >7. The dosage of leucovorin was increased
to 90 mg/m2 every 6 hours. A second administration of CPDG2 was performed. The following day, clinical status of the patient worsened, with
mucositis grade II and cutaneomucous jaundice. At echography, the kidneys size was noted to be normal. Fifteen days after the start of the sixth
MTX cycle, renal and hepatic function had normalized.
During this cycle, 7-OHMTX plasma level was 231 mol/L 24 hours
after the start of the infusion versus a median value of 61 mol/L (range
52132) in previous cycles. In addition, we measured plasma total homocysteine. During this cycle, we observed very high homocysteine
plasma concentrations (normal value in children <12 mol/L): 12
mol/L 24 hours after the start of infusion and a maximum of 50 mol/L
reached 137 hours after the start of the MTX infusion. The homocysteine
plasma level was still 13.4 mol/L 330 hours after the start of the infusion and returned to normal value only 450 hours after the infusion.
About one month after the sixth cycle, the excision of the tumor with
limb salvage was performed. Postoperatively, the estimation of the histologic response, according to the guidelines of Rosen et al.,11 showed that
the patient could be classified as a high responder. After surgery, highdose MTX was resumed at 3 g/m2 for the first cycle, 4 g/m2 for the second, and had been maintained at the total dose (12 g/m2) since the third
postoperative cycle. The patient completed the protocol of high responders (12 postoperative courses) without other complications. MTX plasma concentrations remained within the normal range. All treatments
were stopped in August 2000. Since this time, the clinical and biological
status of the patient are favorable.
Use of the Naranjo probability scale indicated a probable relationship
between the observed complications and MTX therapy in this patient.12

Case Report
A 14-year-old Hispanic boy (59 kg, 1.78 m, body surface area 1.73
m2) was diagnosed with nonmetastatic osteosarcoma of the right tibia in
October 1999.
He was treated according to the OS-SFOP-94 (OsteosarcomaThe
French Society of Pediatric Oncology) protocol. The preoperative chemotherapy consisted of doxorubicin and high-dose MTX (12 g/m2 every
wk). High-dose MTX was administered over 4 hours. A leucovorin rescue (12 mg/m2 every 6 h) was started 20 hours after initiating the MTX
infusion and continued until MTX plasma concentrations fell to <0.2
mol/L. Four hours prior to each high-dose MTX cycle, the patient received hydration with 3 L/m2/day and alkalinization with sodium bicarbonate to raise urine pH values to 7 as required by the protocol. This
protocol allowed for 7 preoperative cycles.
Routine monitoring of MTX serum concentrations was performed according to the MTXTDX method (Abbott Laboratories, Rungis,
France) 24, 48, and 72 hours after the start of the infusion and until the
concentration fell to <0.2 mol/L. Because of the administration of
CPDG2, a cross-reactivity between MTX and MTX metabolites produced by CPDG2 may be observed, leading to an overestimation of
MTX plasma concentrations. As a result, in such cases, only HPLC will
accurately determine MTX concentrations. We then used an HPLC
method validated in our unit to measure the concentrations.9 To estimate
the metabolism of MTX, this HPLC method was used to evaluate serum
concentrations of 7-hydroxymethotrexate (7-OHMTX), the main metabolite of MTX, at the same sampling times.
Because of cardiac insufficiency diagnosed in the boy before the first
cycle of doxorubicin, this drug was replaced by ifosfamide 3 g/m2 plus
etoposide 75 mg/m2, administered alternately with MTX. Liver and kidney function were normal before starting chemotherapy (Table 1).10
The first 5 cycles of high-dose MTX were well tolerated. The MTX
plasma concentration measured 24 hours after the start of the sixth MTX
cycle was 657 mol/L compared with 3.3 mol/L for the first cycle

Table 1. Patients Biological Parameters During the Sixth Cycle of High-Dose Methotrexate
Methotrexate Treatment (day)
6
7
15

Before

1a

0.8

7.06

9.45

10.7

9.8

1.32

Creatinine clearanceb (mL/min/1.73 m2)

157

17.8

13.3

11.7

12.7

95.4

114

177

BUN (1842 mg/dL)

14.4

91.8

120

141

157

47.4

36.6

16.8

Uric acid (34 mg/dL)

1.76

2.2

93 000

127 000

396 000

2700

2700

1404

1431

Parameter
Serum creatinine level
(normal 0.71.4 mg/dL)

3.98

11.3

8.2

4.8

3.3

1.66

AST (540 UI/L)

69

1705

1372

1001

816

59

ALT (756 UI/L)

112

3000

2893

2905

2906

16

20

1.1

0.71

201

Platelets (/mm3)
Leukocytes ( 103/mm3)
Neutrophils ( 103/mm3)
MTX concentration (mol/L)

657

614

24.1

34.2

0.825

0.4

0.3

7-OHMTX concentration (mol/L)

233

244

2.5

8.8

1.3

0.935

0.24

Homocysteine concentration (mol/L)

12.1

25.4

33.3

49.5

13.4

7.3

ND

BUN = blood urea nitrogen; ALT = alanine aminotransferase; AST = aspartate aminotransferase; MTX = methotrexate; ND = not determined; 7OHMTX = 7-hydroxymethotrexate.
a
After the start of the MTX infusion.
b
Calculated according to the formula of Schwartz.10

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H Peyriere et al.

Discussion
The etiology of delayed MTX elimination in our patient
remains unknown since he did not receive medication
known to be nephrotoxic or to alter the clearance of MTX.
Other concomitant medications administered during cycle
6 of high-dose MTX were metoclopramide and tropisetron
for vomiting and acetaminophen and nalbuphine for pain.
We can therefore rule out the involvement of these drugs
in the complications shown by our patient.
TOXICITIES OF HIGH-DOSE METHOTREXATE

Our patient showed acute renal failure and hepatitis, 2

well-documented toxicities observed with high-dose MTX.
MTX is mainly excreted by renal elimination, although the
exact mechanism is unclear. At high concentrations, renal
clearance is constant and exceeds that of inulin clearance,
indicating that the drug is not only filtered but also actively
secreted by renal tubular cells.13
The severity of MTX toxicity is related to the duration
of exposure to a concentration that exceeds the tissue-dependent threshold concentration. For kidneys, the concentration threshold may be 104 molar ranges when the urine
is alkaline, possibly lower when it is acid.13
Transient increase in creatinine has been observed to
complicate 1.4% of the 376 preoperative courses of highdose MTX in 97 patients with osteosarcoma, and delayed

excretion occurred in 15% of those patients.14 In one study,

the toxicity of high-dose MTX was estimated in 18 patients with osteosarcoma and in 22 patients with acute
lymphoblastic leukemia (ALL).15 Myelosuppression was
more frequently observed in patients with ALL, and
nephrotoxicity was comparable in the groups. However,
hepatotoxicity (serum transaminase elevations >350 UI/L)
was more frequent in osteosarcoma (32% of courses) than
ALL (6%), suggesting a dose relationship.
Mucositis, an adverse effect presented by our patient, is
more frequent in patients with high-risk MTX concentrations.16
METHOTREXATE CONCENTRATIONS

After the fourth and fifth cycles of MTX, plasma concentrations did not return to normal as quickly as in prior
cycles. Indeed, the threshold value of 0.2 mol/L was
reached only 125 and 111 hours, respectively, after the start
of the infusion, without renal dysfunction. This may have
predicted acute toxicity during the sixth cycle. During this
cycle, MTX plasma concentrations were greatly elevated.
Thus, the first concentration measured 24 hours after the
start of the infusion was 657 mol/L. During 85 hours, the
concentrations remained >600 mol/L. Plasma concentrations >1 mol/L approximately 42 hours after the start of
MTX have been associated with increased risk of toxicity
if only the standard leucovorin rescue is administered.16
One study identified factors associated with
high-risk MTX plasma concentrations and
with toxicity in patients with ALL.16 High-risk
MTX concentrations were significantly associated with a higher MTX AUC, low urine pH,
emesis, low MTX clearance, low urine output
relative to intake, use of antiemetics during the
MTX infusion, and concurrent intrathecal therapy (all p values <0.01). Our patient presented
some of these factors, especially the increase
of MTX AUC during the cycle with complications and the use of antiemetics. A third space,
such as ascites, pleural effusion, or edema, has
been shown to store MTX at concentrations
higher than those in plasma. The slow release
from this space has been associated with a prolonged low plasma MTX concentration, which
has been implicated in the development of toxicity.17 Such complications were not observed
in our patient.
In another study of children treated for osteosarcoma, MTX plasma concentrations >700
mol/L at the end of a 6-hour infusion were
associated with a higher survival rate.18 Some
authors have proposed that, in patients with osteosarcoma, it is important to reach the highest
possible plasma MTX concentrations (at least
>700 mol/L) and that the dose should be adjusted to individual clearance.18,19 In our paFigure 1. A: plasma concentrations of MTX. B: plasma concentrations of homocysteine.
Data observed during the sixth cycle of MTX treatment. MTX = methotrexate.
tient, although the concentrations at the end of
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Methotrexate Intoxication in a Child

the infusion for preoperative cycles were not available, the

very high values observed during the sixth cycle could have
conditioned the efficacy of MTX and the clinical outcome.
It is difficult to determine with certainty whether the patient
was a high responder or whether the exposure to excessive
plasma concentrations observed increased the tumor lysis.
For the postoperative MTX cycles, we measured the
plasma concentrations at the end of the 4-hour infusion:
the mean SD was 911 326 mol/L, which is compatible with a good clinical outcome.
7-HYDROXYMETHOTREXATE PLASMA CONCENTRATIONS

Administration of very high-dose MTX permitted detection of 7-OHMTX. This compound was found to have
200-fold less inhibitory activity of dihydrofolic acid reductase than MTX itself.2 In addition, 7-OHMTX, just like
MTX, is excreted by kidneys, but is 4 times less soluble
than MTX. Therefore, a suggested mechanism for delayed
elimination is precipitation of 7-OHMTX in the renal
tubule leading to renal dysfunction.2 Some preclinical rat
data suggest a toxic effect of 7-OHMTX on kidneys and
liver cells.20
We measured 7-OHMTX at the same sampling times as
MTX. During the cycle with complications, the 7-OHMTX
plasma concentration was much higher 24 hours after the
start of the infusion than the median value in previous cycles. It seems that 7-hydroxylation of MTX increases in
presence of high MTX plasma concentrations; however,
this metabolic pathway seems rate-limited. Moreover, 7OHMTX has been found to be a substrate for CPDG2. After
administration of the first dose of CPDG2, the 7-OHMTX
plasma concentrations declined from 245 to 2.5 mol/L
within 16 hours. Even if the increase of 7-OHMTX plasma concentrations during the sixth cycle could have contributed in part to the adverse effects, the decrease in the
relative amount observed after administration of CPDG2
probably limited the renal toxicity of this metabolite.
HOMOCYSTEINE CONCENTRATIONS

The pharmacodynamic effect of MTX in our patient

was confirmed by estimation of homocysteine plasma concentrations, which represent a marker of the inhibition of
folate-dependent enzymes. This parameter rapidly increases after high-dose MTX administration, the peak being observed 24 hours after the start of MTX infusion.7,8 However, the increased homocysteine levels induced by MTX are
normalized after rescue therapy with folinic acid.7 During
the cycle with complications, homocysteine plasma concentrations remained over the baseline value for 330 hours.
In a study performed using children treated with MTX for
osteosarcoma, the peak of plasma total homocysteine was
observed 24 hours after the infusion. The homocysteine
level increased from 9.9 1.1 mol/L at baseline to 15.2
2.1 mol/L at 24 hours.8 In our patient, during other MTX
cycles, the mean homocysteine plasma concentration SD
after 24 hours was 11.2 2.2 mol/L. We did not observe
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the peak 24 hours after the start of the MTX infusion, as

described in the literature, but instead noted the peak after
48 hours. Hence, the monitoring of homocysteine concentrations could provide a tool to evaluate the responder status. However, further studies are necessary to define the
usefulness of routine measurements of homocysteine plasma concentrations in children receiving high doses of
MTX for osteosarcoma.
TREATMENT OF METHOTREXATE INTOXICATION

Leucovorin alone may not prevent the development of

life-threatening toxicities in patients with MTX concentrations persistently >10 mol/L at 48 hours.2 Leucovorin
doses >1000 mg/m2 every 6 hours are associated with cardiac arrhythmias resulting from hypercalcemia.21 Moreover,
if administration of leucovorin is effective in prevention of
hematologic toxicity, it has no effect on MTX elimination.
As a consequence of our patients high MTX plasma concentrations observed, we used 2 specific treatments indicated for MTX delayed elimination and/or neurotoxicity.
The first treatment involves the use of CPDG2, which
hydrolyzes MTX in nontoxic metabolites and decreases
the incidence and severity of systemic complications. In
one study, CPDG2 rescue was well tolerated, safe, and very
effective in preventing severe or life-threatening MTX toxicity in 20 patients.4 In patients with osteosarcoma, MTX
plasma concentrations decreased from a median of 89
mol/L (range 2.4 460) immediately before CPDG2 treatment to a median of 1 mol/L (<0.05 4.7) 15 minutes after CPDG2 administration. Adverse effects described by 4
patients included warm, tingling fingers; head pressure;
flushing; shaking; and minimal burning of the face and extremities. The authors concluded that the efficacy of
CPDG2 may be optimal if administered within 4872
hours from the start of the MTX infusion.
In our team, we recommend that CPDG2 be administered if MTX plasma concentrations are >10 mol/L 42
hours after the start of the infusion or renal failure (defined
by a serum creatinine >1.5-fold the baseline value or creatinine clearance <60 mL/min/m2) associated with delayed
elimination of MTX is observed. If either of these parameters is met, CPDG2 may be administered within 96 hours
after starting MTX infusion. Our patient received 2 injections of CPDG2. The first led to a significant decrease in
MTX plasma concentrations, as previously reported.4 As
observed by Widemann et al.,4 the second dose of CPDG2
did not result in a further reduction in MTX plasma concentrations in our patient. A small rebound increase in
MTX plasma concentrations was observed. Nevertheless,
this treatment certainly contributed to the rapid recovery of
and the moderate myelosuppression observed in our patient.
The second treatment option involves aminophylline. Experience with aminophylline is more limited. In 2 reports,
this drug has been shown to be effective and safe for treatment of acute neurotoxicity related to high-dose MTX in
children.5,22 Cronstein et al.23 proposed a mechanism for the

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H Peyriere et al.

benefit of aminophylline in high-dose MTX neurotoxicity:

increased adenosine may account for some of the neurotoxicity, and aminophylline is a competitive antagonist for
adenosine receptors. Our patient did not show neurologic
disorders. The release of adenosine induced by MTX can, in
turn, decrease the glomerular flow rate. Aminophylline, acting as an adenosine antagonist, may improve renal function.
To our knowledge, as of January 2004, this is the first
report of the use of CPDG2 and aminophylline in combination. At this time, the guidelines for the use of such therapeutic procedures remain to be clearly determined and
evaluated.
Summary
Development and treatment of MTX toxicity in our patient observed during one cycle of high-dose MTX is not
predictive of the tolerability of further courses. Optimal
management of such complications using specific therapeutic intervention (CPDG2, aminophylline) allowed us to
minimize the systemic adverse effects observed.
Hlne Peyriere PharmD PhD, Lecturer in Clinical Pharmacy, Department of Medical Pharmacology and Toxicology, Lapeyronie Hospital, Montpellier, France
Marylne Cociglio PharmD PhD, Lecturer in Clinical Pharmacology, Department of Medical Pharmacology and Toxicology, Lapeyronie Hospital
Genevive Margueritte MD, Physician, Department of Pediatric
Oncology, Arnaud de Villeneuve Hospital, Montpellier
Catherine Vallat PhD, Biologist, Laboratory of Biochemistry, SaintEloi Hospital, Montpellier
Jean-Pierre Blayac MD PhD, Professor in Clinical Pharmacology, Department of Medical Pharmacology and Toxicology, Lapeyronie Hospital
Dominique Hillaire-Buys MD PhD, Lecturer in Clinical Pharmacology, Department of Medical Pharmacology and Toxicology, Lapeyronie Hospital
Reprints: Hlne Peyriere PharmD PhD, Service de Pharmacologie Mdicale et Toxicologie, Hpital Lapeyronie, 371 avenue du
Doyen Gaston Giraud, 34295 Montpellier Cedex 5, France, fax 334-67-33-67-51, h-peyriere@chu-montpellier.fr

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2. Chu E, Allegra CJ. Antifolates. In: Chabner BA, Longo DL, eds. Cancer
chemotherapy and biotherapy: principles and practice. 2nd ed. Philadelphia: JB Lippincott, 1995:109-48.
3. Chan H, Evans WE, Pratt CB. Recovery from toxicity associated with
high-dose methotrexate: prognostic factors. Cancer Treat Rep 1977;61:
797-804.
4. Widemann BC, Balis FM, Murphy RF, Sorensen JM, Montello MJ,
OBrien M, et al. Carboxypeptidase G2, thymidine and leucovorin rescue in cancer patients with methotrexate-induced renal dysfunction. J
Clin Oncol 1997;15:2125-34.
5. Bernini JC, Fort DW, Griener JC, Kane BJ, Chappell WB, Kamen BA.
Aminophylline for methotrexate-induced neurotoxicity. Lancet 1995;
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6. Guttormsen AB, Ueland PM, Lonning PE, Mella O, Refsum H. Kinetics
of plasma total homocysteine in patients receiving high-dose methotrexate therapy. Clin Chem 1998;44:1987-9.
7. Refsum H, Ueland PM, Kvinnsland S. Acute and long term effects of
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8. Broxson EH, Stork LC, Allen RH, Stabler SP, Kolhouse JF. Changes in
plasma methionine and total homocysteine levels in patients receiving
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and 7-hydroxymethotrexate by liquid chromatography for routine monitoring of plasma levels. J Chromatogr B Biomed Appl 1995;674:101-10.
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method for estimating the probability of adverse drug reactions. Clin
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14. Saeter G, Alvegard TA, Elomaa I, Stenwig AE, Holmstrom T, Solheim
OP. Treatment of osteosarcoma of the extremities with the T-10 protocol,
with emphasis on the effects of preoperative chemotherapy with singleagent high-dose methotrexate: a Scandinavian Sarcoma Group study. J
Clin Oncol 1991;9:1766-75.
15. Ridolfi L, Barisone E, Vivalda M, Vivenza C, Brach Del Prever A,
Leone L, et al. Toxicity of high dose methotrexate repeated infusions in
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16. Relling MW, Fairclough D, Ayers D, Crom WR, Rodman JH, Pui CH, et
al. Patient characteristics associated with high-risk methotrexate concentrations and toxicity. J Clin Oncol 1994;12:1667-72.
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18. Bacci G, Ferrari S, Delepine N, Bertoni F, Picci P, Mercuri M, et al. Predictive factors of histologic response to primary chemotherapy in osteosarcoma of the extremity: study of 272 patients preoperatively treated
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22. Peyriere H, Poiree M, Cociglio M, Margueritte G, Hansel S, HillaireBuys D. Reversal of neurologic disturbances related to high-dose
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EXTRACTO
OBJETIVO: Describir la evolucin y el manejo de la toxicidad con
metotrexato (MTX) en un nio de 14 aos con osteosarcoma tratado con
dosis altas de este frmaco.
RESUMEN DEL CASO: Se observ un caso de intoxicacin severa durante el
sexto ciclo de dosis altas de MTX. El nio present niveles altos de
MTX en plasma, fallo renal agudo, y hepatitis seguido por mucositis y
mielosupresin moderada. La alcalinizacin de la orina y dosis
aumentadas de leucovorin no disminuyeron los niveles en plasma de
MTX o previnieron toxicidades sistmicas. Por lo tanto, se administr
carboxipeptidasa G2 y aminofilina como un segundo intento de
estrategia de rescate. Se observ una recuperacin de los sntomas
clnicos y normalizacin de las anormalidades biolgicas dentro de 2
semanas. Se realiz una ciruga para salvar la extremidad, lo que
permiti clasificar al paciente cmo uno de buena respuesta a MTX.
Luego de esto, se volvi a iniciar la terapia con MTX lo que llev a una

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Methotrexate Intoxication in a Child

recuperacin clnica del paciente. Al mismo tiempo, se midieron niveles

en plasma de homocistena, un marcador del efecto farmacodinmico de
MTX. Durante la intoxicacin, los niveles en plasma de homocistena
estuvieron aumentados significativamente, paralelo a los niveles en
plasma excesivos de MTX observados.
DISCUSIN: De acuerdo a los niveles excesivos de MTX medidos en este
paciente, conjuntamente con los efectos adversos clnicos (mucositis) y
biolgicos (hepatitis, dao renal) observados, los autores sugieren que
MTX pudo ser una causa de estas complicaciones. El uso de la escala de
probabilidad de Naranjo indic una relacin probable entre las
complicaciones y MTX.
CONCLUSIONES: Este caso demuestra que las complicaciones severas
observadas durante un ciclo de dosis altas de MTX no es predictivo de
la tolerabilidad de cursos futuros. Se debe considerar un manejo ptimo
de estas complicaciones utilizando intervenciones teraputicas
especficas.
Juan F Feli
RSUM

Dcrire la prise en charge dune intoxication au mthotrexate

chez un patient de 14 ans trait pour un ostosarcome avec du
mthotrexate haute dose.
RSUM DU CAS: Au cours de la sixime cure de mthotrexate haute
dose, des taux plasmatiques trs levs de mthotrexate ont t mesurs,
associs une insuffisance rnale, une hpatite, une mucite, et une
mylosuppression modre. Lintensification de la diurse alcaline et
laugmentation des doses dacide folinique nont pas t suffisant pour
OBJECTIF:

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prvenir une toxicit systmique. De la carboxypeptidase G2 et de

laminophylline ont donc t administrs en tant que stratgie de
sauvetage de seconde intention. En 2 semaines, les symptmes cliniques
ont rgress et les paramtres de laboratoires se sont normaliss. Une
chirurgie avec conservation du membre a t ralis et ce patient a t
class parmi les bons rpondeurs au mthotrexate. Les cures de
mthotrexate ont donc t reprises conduisant une gurison du patient.
Par ailleurs, les taux plasmatiques dhomocystine ont t mesurs en
tant que marqueur de lactivit antifolate du mthotrexate. Pendant
lintoxication, des taux plasmatiques dhomocystine significativement
levs ont t mesurs, en relation avec les taux plasmatiques trs levs
de mthotrexate.
DISCUSSION: Compte tenu des taux plasmatiques trs levs de
mthotrexate mesurs chez ce patient et du tableau clinique (mucite) et
biologique (hpatite, insuffisance rnale) observ, nous supposons que le
mthotrexate a pu tre responsable de ces complications. Lutilisation de
lalgorithme dimputabilit des effets indsirables de Naranjo a permis
de conclure une relation probable entre les effets indsirables observs
et le mthotrexate.
CONCLUSIONS: Cette observation montre que des complications svres
observes lors dune cure de mthotrexate haute dose ne sont pas
prdictives de la tolrance du produit lors de cures ultrieures. Une prise
en charge optimale associant des thrapeutiques classiques (acide
folinique, hydratation) et spcifiques (aminophylline, carboxypeptidase
G2) peut tre envisager en pareil cas.

The Annals of Pharmacotherapy

Hlne Peyriere

2004 March, Volume 38

427