2222
High-Dose Methotrexate-Induced Nephrotoxicity in
Patients with Osteosarcoma
Incidence, Treatment, and Outcome
Brigitte C. Widemann, M.D.1
Frank M. Balis, M.D.1
Beate Kempf-Bielack, M.D.2
Stefan Bielack, M.D.2
Charles B. Pratt, M.D.3*
Stefano Ferrari, M.D.4
Gaetano Bacci, M.D.4
Alan W. Craft, M.D.5
Peter C. Adamson, M.D.6
1
Pediatric Oncology Branch, National Cancer In-
stitute, Bethesda, Maryland.
2
Department of Pediatric Hematology and Oncol-
ogy, University Children’s Hospital Muenster,
Muenster, Germany.
3
Department of Hematology/Oncology, St. Jude Chil-
dren’s Research Hospital, Memphis, Tennessee.
4 among those patients was 4.4% (3 of 68 patients). Dialysis-based methods of MTX
Istituto Ortopedico Rizzoli, Bologna, Italy.
5
Department of Child Health, Royal Victoria Infir-
mary, Newcastle upon Tyne, United Kingdom.
6
Division of Clinical Pharmacology and Therapeu-
tics, Children’s Hospital of Philadelphia, Philadel-
phia, Pennsylvania.
The authors thank Dr. James Balow at the National
Institute of Diabetes, and Digestive, and Kidney
Disorders for helpful suggestions during the prep-
aration of this article.
This article is dedicated to the memory of Dr.
Charles Pratt, who devoted his extraordinary ca-
reer to the treatment of children with cancer and
the development of more effective therapies for
childhood cancers.
*Deceased.
Address for reprints: Brigitte C. Widemann, M.D.,
Pediatric Oncology Branch, National Cancer Insti-
tute, 10 Center Drive, Building 10, Room 13C103,
Bethesda, MD 20892-1920; Fax: (301) 480-8871;
E-mail: bw42y@nih.gov
Received January 14, 2004; revision received Feb-
ruary 19, 2004; accepted March 4, 2004.
© 2004 American Cancer Society
DOI 10.1002/cncr.20255
Published online 19 April 2004 in Wiley InterScience (www.interscience.wiley.com).
BACKGROUND. High-dose methotrexate (HDMTX)-induced renal dysfunction can
be life threatening, because it delays methotrexate (MTX) excretion, thereby exac-
erbating the other toxicities of MTX. HDMTX-induced nephrotoxicity has been
managed with high-dose leucovorin, dialysis-based methods of MTX removal,
thymidine, and with the recombinant enzyme, carboxypeptidase-G2 (CPDG2),
which cleaves MTX to inactive metabolites. The objectives of the current study
were to estimate the current incidence of HDMTX-induced renal dysfunction in
patients with osteosarcoma and to compare the efficacy and recovery of renal
function for dialysis-based methods of MTX removal with treatment using CPDG2.
METHODS. The literature was reviewed for osteosarcoma trials, use of dialysis-
based methods for MTX removal, and reports of MTX-induced nephrotoxicity,
including information regarding recovery of renal function. Clinical trial databases
of select osteosarcoma studies were reviewed. The efficacy of CPDG2 and renal
recovery after CPDG2 rescue was obtained from the database of a compassionate-
release trial.
RESULTS. Approximately 1.8% of patients with osteosarcoma (68 of 3887 patients)
who received HDMTX developed nephrotoxicity Grade ⱖ 2. The mortality rate
removal were used frequently but had limited effectiveness in removing MTX
compared with the rapid reductions ⬎ 98% in plasma MTX concentrations
achieved with CPDG2. CPDG2 did not appear to increase the time to recovery of
renal function compared with supportive treatment that included dialysis-based
methods.
CONCLUSIONS. HDMTX-induced renal dysfunction continues to occur in approx-
imately 1.8% of patients with osteosarcoma who are treated on clinical protocols
with optimal supportive care. For patients with delayed MTX excretion and high
plasma MTX concentrations, CPDG2 should be considered over hemodialysis to
lower plasma MTX concentrations rapidly and efficiently. Cancer 2004;100:
2222–32. © 2004 American Cancer Society.
KEYWORDS: methotrexate toxicity, renal dysfunction, hemodialysis, hemoperfusion,
carboxypeptidase-G2, high-dose methotrexate.
M ethotrexate (MTX), a classic antifol, is one of the most widely
used and well studied anticancer agents. The administration of
MTX doses ⱖ 1000 mg/m2 combined with leucovorin (LV) rescue is
defined as high-dose methotrexate (HDMTX). HDMTX is an impor-
tant component of treatment for a variety of malignancies, including
acute lymphoblastic leukemia (ALL), lymphoma, osteosarcoma,
breast carcinoma, and head and neck carcinoma.1–5
HDMTX with LV rescue is tolerated well by the majority of pa-
 HDMTX Nephrotoxicity in Osteosarcoma/Widemann et al.
tients. However, the development of HDMTX-induced
acute renal dysfunction, which is mediated by the
precipitation of MTX and its metabolites in the renal
tubules,6 – 8 is a potentially life-threatening complica-
tion. MTX is cleared primarily by renal excretion,9 and
renal dysfunction results in delayed MTX excretion
and sustained, elevated plasma MTX concentrations,
which may lead to a marked enhancement of the other
toxicities of MTX, especially myelosuppression, mu-
cositis, hepatitis, and dermatitis.2,3,9 –11 Nephrotoxicity
secondary to HDMTX was responsible primarily for its
morbidity and mortality observed during the 1970s. In
a single-institution study of 64 patients, there were 3
deaths secondary to renal dysfunction,12 and 29 of 498
patients who were treated on National Cancer Insti-
tute protocols died secondary to HDMTX, for a mor-
tality rate of 6%.13
Uniform institution of aggressive hydration, alka-
linization, and pharmacokinetically guided LV rescue
reduced the morbidity rate significantly in patients
receiving HDMTX.14 However, reports of significant
morbidity and mortality secondary to HDMTX-in-
duced renal dysfunction have continued to appear in
the literature.11,15–19 Because there is no centralized
reporting mechanism for MTX nephrotoxicity, to our
knowledge the current incidence of HDMTX-induced
renal dysfunction is unknown.
Conventional treatment for HDMTX-induced re-
nal dysfunction includes a prompt increase in the LV
dose based on plasma MTX concentrations9,20 and the
continuation of hydration and alkalinization, provided
adequate urine output can be maintained. Hemodial-
ysis-based methods of MTX removal have been
described for over 20 years.21–29 More recently, car-
boxypeptidase-G2 (CPDG2), a recombinant bacterial
enzyme30,31 that hydrolyzes MTX to the inactive metab-
olite 2,4-diamino-N10-methylpteroic acid (DAMPA),32,33
has become available as an investigational new drug
for the treatment of HDMTX-induced renal dysfunc-
tion. When administered to patients with MTX-in-
duced renal dysfunction, CPDG2 lowers plasma MTX
concentrations within 15 minutes of administration
by a median of 98.7% (range, 95.6 –99.6%).27,34 –36
With the advent of new therapeutic strategies for
patients with HDMTX-induced renal dysfunction, a
reassessment of the incidence, treatment, and out-
come of MTX-induced nephrotoxicity is needed. Pa-
tients with osteosarcoma usually receive single-agent
HDMTX as a short, intravenous infusion during a che-
motherapy cycle and, thus, represent an ideal popu-
lation to study this toxicity, because their develop-
ment of renal dysfunction can be attributed to the
HDMTX. The objectives of the current study were 1) to
determine the current incidence of HDMTX-induced
2223
renal dysfunction in patients with osteosarcoma, 2) to
review the use and efficacy of dialysis-based methods
of MTX removal in patients with HDMTX-induced
renal dysfunction, 3) to determine the time to recovery
of renal function in patients with HDMTX-induced
renal dysfunction after treatment with supportive and
dialysis-based methods, and 4) to compare the effi-
cacy of dialysis-based methods and the time to renal
recovery after supportive treatment with the efficacy
and renal recovery after treatment with CPDG2.
MATERIALS AND METHODS
Current Incidence of HDMTX-Induced Renal Dysfunction
in Osteosarcoma
Databases from the Cooperative German-Swiss-Aus-
trian Osteosarcoma Study (COSS),15,37– 44 the Euro-
pean Osteosarcoma Intergroup (EOI),45– 49 the Rizzoli
Institute (Italy),50 – 65 and the St. Jude Children’s Re-
search Center (St. Jude)66 – 68 were reviewed. Informa-
tion regarding the number of patients in which renal
dysfunction after HDMTX was reported, the severity
and treatment of renal dysfunction, and the time to
recovery of renal dysfunction was collected. COSS
screened their database for patients with renal toxicity
ⱖ Grade 2, the Rizzoli Institute screened their data-
base for patients with serum creatinine levels greater
than the upper limit of normal (ULN), and the EOI and
St. Jude screened their databases for patients with
serious and significant renal toxicity. Renal toxicity
was graded using World Health Organization criteria
(Grade 1, serum creatinine levels ⬍ 1.5 ⫻ ULN; Grade
2, 1.5–3.0 ⫻ ULN; Grade 3, 3.1– 6.0 ⫻ ULN; and Grade
4, ⬎ 6.0 ⫻ ULN).
The literature was reviewed using the MEDLINE
and CancerLit databases (1980 –2002). Publications of
clinical osteosarcoma trials that contained HDMTX
that were performed after 1980, a time during which
hydration and alkalinization were administered rou-
tinely as part of HDMTX treatment, were identified.
Data were included only from those studies in which
the number of patients entered and the number of
HDMTX-related nephrotoxic events were reported.
Use and Effectiveness of Dialysis-Based Methods for
MTX Removal
The literature was reviewed using MEDLINE and Can-
cerLit databases (1980 –2002) for reports or case series
describing the use of dialysis-based methods for MTX
removal in patients with MTX-induced renal dysfunc-
tion.
2224 CANCER May 15, 2004 / Volume 100 / Number 10
Recovery of Renal Function after MTX-Induced Renal
Dysfunction
To define the time course of recovery of renal function
after MTX-induced renal dysfunction in patients who
were treated with supportive and hemodialysis/filtra-
tion-based methods or with the addition of CPDG2,
publications and clinical trial database data were an-
alyzed that provided a definition for recovery of renal
function and included the number of days to recovery
of renal function.
MTX Pharmacokinetics and Recovery of Renal Function
after CPDG2 Administration
Information regarding MTX pharmacokinetics and
clinical outcome after the administration of CPDG2 for
HDMTX-induced renal dysfunction was obtained
from the database of an ongoing, compassionate-re-
lease trial of CPDG2 sponsored by the Cancer Therapy
Evaluation Program of the National Cancer Institute
and was published previously.34,35
RESULTS
Current Incidence of HDMTX-Induced Renal Dysfunction
in Osteosarcoma
Twenty published clinical trials, which accrued pa-
tients after 1980, contained data that included the
number of patients entered and the incidence of renal
toxicity (Table 1). The median incidence of reported
renal toxicity in the individual studies was 1.5%
(range, 0.0 –12.4%). When renal events were described
as cases or cycles, the assumption was made that each
cycle or case corresponded to an individual patient.
When combined with additional data provided in this
report (Table 1), there were 3887 patients enrolled on
osteosarcoma trials in which renal toxicity data were
available. Sixty-eight of those 3887 patients (1.8%) de-
veloped nephrotoxicity that was either ⱖ Grade 2 or
significant enough to be reported, and 23 patients
(0.6%) developed Grade 3 or 4 toxicity. The manage-
ment of HDMTX-induced renal dysfunction was de-
scribed for 24 patients. Three patients received
CPDG2, 1 patient was treated with hemoperfusion (1
death), 1 patient was treated with plasmapheresis, 2
patients received CPDG2 and underwent high-flux he-
modialysis or hemodialysis, and 17 patients were
treated with supportive measures that included alka-
linization, hydration, and LV rescue only. There were 3
deaths attributable to HDMTX-induced renal dysfunc-
tion in 68 patients, for a 4.4% mortality rate (0.08%
mortality in all patients who received HDMTX).
Use of Dialysis-Based Methods to Remove MTX
The efficacy of mechanical methods of MTX removal
is summarized in Table 2. Over the past 20 years, 30
publications reported results of dialysis-based meth-
ods of MTX removal in 49 patients. The most fre-
quently utilized single methods used were hemodial-
ysis (10 patients), high-flux hemodialysis (nine
patients), and charcoal hemoperfusion or charcoal he-
mofiltration (seven patients). Sixteen patients were
treated with multiple modalities and therefore are ref-
erenced more than once in Table 2.
Peritoneal dialysis alone resulted in a minimal
decrease in plasma MTX concentrations.21,22 The use
of other single-modality methods of MTX removal re-
sulted in a median decrease in plasma MTX concen-
trations of 52% (range, 26 – 82%). Dialysis-based meth-
ods were used for up to 14 days. The use of high-flux
hemodialysis resulted in the greatest decrease in
plasma MTX concentrations (median, 75.7%; range,
42–94%) within the shortest time (median, 4 hours;
range, 4 –12 hours). Only 3 patients had a decrease
⬎ 90% in MTX concentrations with the use of a single
method in 1 dialysis session.28,69,70
Increases in MTX plasma concentrations after the
completion of dialysis-based methods were reported
and quantified in seven reports. Rebound increases in
postdialysis plasma MTX concentrations by 10 –221%
of the postprocedure MTX levels21,71,72 and to 90 –
100% of the preprocedure MTX levels were report-
ed.23,24,26,73 Reported complications from the various
dialysis methods included cardiac arrest in one pa-
tient after plasma exchange,23 bleeding from the cath-
eter exit site,24 anemia,24,25 thrombocytopenia,24,74
and hypokalemia and severe hypophosphatemia,70
but the incidence of these complications could not be
estimated accurately.
Recovery of Renal Function with Current Supportive
Treatment
For 31 patients described in 13 publications and 9
additional patients treated on COSS trials who re-
ceived treatment with supportive measures (including
LV), and thymidine administration or dialysis-based
removal of MTX in some patients, but not CPDG2,
sufficient data regarding recovery of renal function
were available (Table 3). The studies defined recovery
of renal function differently as recovery of function (1
patient), serum creatinine 1.5 times the baseline level
(20 patients), serum creatinine 1.7 times the baseline
level (1 patient), the ability to discontinue dialysis (2
patients), normal serum creatinine levels (7 patients),
or a return of serum creatinine to pretreatment (base-
line) levels (9 patients). The reported peak serum cre-
atinine concentrations were higher for the 12 patients
who underwent dialysis-based methods (median se-
rum creatinine, 3.9 mg/dL; range, 1.7–7.6 mg/dL)
compared with 20 patients who did not undergo dial-
 HDMTX Nephrotoxicity in Osteosarcoma/Widemann et al. 2225

TABLE 1
Incidence of High-Dose Methotrexate-Induced Nephrotoxicity in Patients with Osteosarcoma

No. of No. of HDMTX renal

patients planned toxicity Mortality
MTX dose on courses/ (no. of
Study/yrs of study (g/m2) HDMTX patient No. % Details of renal toxicity deaths) Reference(s)

Results of a review of the literature (1980–2002)

COSS
1979–1982 12.0 189a 14 2 patientsa 1.0 Death, delayed MTX elimination 2b 15, 37, 39
1982–1984 12.0 141a 14 7 cyclesa 5.0 Delay ⱖ 7 days in subsequent CT for delayed MTX — 39
elimination (3 patients), elevated serum creatinine (4
patients)
France
1984–1985 8.0–12.0 52 10 0 0.0 — — 76
1982–1992 8.0, 12.0, 18.0 71 16 6 patients 8.5 Delayed MTX elimination but no severe MTX toxicity — 77
Scandinavia Sarcoma Group
1982–1989 8.0–12.0 97 4 5 cycles 5.2 Grade 1–2 (3 patients), Grade 3 (2 patients), all transient — 78, 79
Norwegian Radium Hospital
1981–1995 8.0–12.0 103 — 2 patients 1.9 ”Moderate” increase in creatinine, no further MTX (1 patient), 1 80
fatal HDMTX toxicity (1 patient)
EOI
1983–1986 8.0 140 560 total 5 patients 3.6 Grade 2 (3 patients), Grade 3 (2 patients) — 45
(8/patient)
1986–1991 8.0–12.0 192 6 patients 3.1 Severe renal impairment (2 patients)c — 48
Rizzoli Institute
2
1980–1983 0.2/2.0 110 — 1 patient 0.9 One patient on MTX 2.0 g/m had renal failure with 1 50
pancytopenia
1983–1986 0.75/7.5 127 2–5 0 0.0 — — 51
OS-2
1986–1989 8.0 164a 5 0 0.0 — — 52, 53, 56, 64,
81, 82
OS-3
1990–1991 10.0 95a 5 5 patientsa 5.0 Delayed MTX elimination with nephrotoxicity, no further MTX — 58, 63
OS-4
a a
1993–1994 6.0 121 6 15 cycles 12.4 Grade 1–2 — 57, 61
1995–1997 12.0 28a 5 1 patienta 3.6 Delayed MTX clearance — 65
POG/DFCI
1982–1984 12.0 77 12 2 3.0 Moderate, 1%; severe, 2%c — 83
TIOS 1
1979–1982 12.5 43 — 0 0.0 — — 84, 85
TIOS 2
1982–1986 12.5 31 — 0 0.0 — — 84, 85
TIOS 3
1986–1989 12.5 24 — 0 0.0 — — 84, 85
OGS
1988–1992 12.0 95 6 4 patients 4.2c — — 86, 87
1992–1996 3.75 7 4 0 0.0 — — 88
Results of a review of clinical trial data
COSS
1980–2000 12.0 2105 25,000 total 24 patients 1.1 Grade 2 toxicity (11 patients), Grade 3 (9 patients), Grade 4 (4 1d —
patients); CPDG2 (3 patients), plasmapheresis (1 patient),
hemodialysis ⫹ CPDG2 (2 patients), supportive (2 patients)
St. Jude’s Children’s
Research Center
1986–1991 12.0 107 812 1 patient 0.9 Grade 3 toxicity: hemodialysis, charcoal hemoperfusion, — 24
thymidine
Rizzoli Institute
1986–1997 — 506 2500 15 patients 3.0 Grade 2 toxicity (14 patients), Grade 3 (1 patients); all patients — —
received LV, hydration, alkalinization, no dialysis, no more
MTX

MTX: methotrexate; HDMTX: high-dose methotrexate; COSS: Cooperative German-Swiss-Austrian Osteosarcoma Study; CT: chemotherapy; EOI: European Osteosarcoma Intergroup; OS-2, OS-3, OS-4: Rizzoli
Institute osteosarcoma studies 2, 3, and 4, respectively; POG: Pediatric Oncology Group/Dana Farber Cancer Institute; TIOS: Treatment and Investigation of Sarcoma; OGS: Osteogenic Sarcoma Studies; CPDG2:
carboxypeptidase-G2; LV: leucovorin.
a
Included in clinical trial data review.
b
Reanalysis by study principal investigator determined that only one death was related to high-dose methotrexate-induced renal dysfunction.
c
Not related conclusively to methotrexate.
d
Death in patient with Grade 4 renal toxicity who underwent hemoperfusion.
2226 CANCER May 15, 2004 / Volume 100 / Number 10

TABLE 2
Efficacy of Methotrexate Removal Methodsa

No. of MTX (␮M) (range)

patients No. of MTX Procedure Postprocedure MTX
Method reported sessions Preprocedure Postprocedure decrease (%) duration rebound increase Reference(s)

Hemodialysis 13 23 1.0 (0.01–511) 0.8 (0.008–206) 50 (3–90) 1 Session (4 hrs ⬍ 20% of postprocedure 21, 23, 24, 26,
to 14 days) to 100% of 27, 69, 89–95
preprocedure levels
(2 patients)b
Hemodiafiltration 4 6 2.0 (0.19–90.0) 0.45 (0.1–2.0) 82 (44–98) 3.5 Days (1 25–43% of 73, 96, 97
session to 5 postprocedure levelsc
days)
High-flux hemodialysis 9 9 71.9 (1.45–1813.0) 42.0 (2.5–293.0) 75.5 (42.0–94.0) 4 Hrs (4–12 hrs) ⱖ 50% of postprocedure 28, 70
levelsh
Charcoal-hemoperfusion 9 12 2.2 (0.18–328.0) 0.75 (0.01–13.5) 53 (14–95) 1 Session (3 hrs 20% of postprocedure (3 20, 23, 69, 71, 98
or hemofiltration to 7 days) patients) to 90% of
preprocedure levelsd
Plasma resin perfusion 1 1 2.9 1.9 35 8 Hrs 93% of preprocedure 72
levels (1 patient)e
Peritoneal dialysis 2 2 1.77 (0.53–3.0) Minimal Minimal 4.5 Days (2–7 — 21, 22
decrease decrease days)
Exchange transfusion or 10 22 3.8 (0.12–32.0) 2.3 (0.12–37.0) 26 (0–72) 1 Session (5 hrs 20% of postprocedure 23, 74, 93, 96,
plasma exchange to 1 session) levels (3 patients)f 97, 99, 100
Charcoal-hemoperfusion/ 8 10 12.7 (0.9–390.0) 2.2 (0.2–14.0) 78 (38–98) 1.0 Day (6 hrs to 10% and 56–221% (1 20, 23–26, 72,
hemofiltration and 6.25 days) patient each) of 92, 101
hemodialysis postprocedure levelsg

MTX: methotrexate.
a
Published literature from 1977 to 2002 on methods and their efficacy used to remove methotrexate from patients with renal dysfunction after methotrexate administration. The median values for plasma
methotrexate concentrations preprocedure and postprocedure, % decrease in methotrexate concentration, and dialysis session duration are reported with the range shown in parenthesis.
b
See Hande et al.21 and Bouffet et al.23
c
See Jambou et al.73
d
See Bouffet et al.23 and Gibson et al.71
e
See Greil et al.72
f
See Bouffet et al.23
g
See Relling et al.24 and Kawabata et al.26
h
See Wall et al.28

ysis (median serum creatinine, 2.2 mg/dL; range, 0.9 – 98.7%) in plasma MTX concentrations, as measured
8.95 mg/dL). Patients with osteosarcoma who were by high-pressure liquid chromatography due to the
treated on COSS studies had a greater degree of renal interference of MTX metabolites with commercially
dysfunction compared with the patients reported by available immunoassays. Plasma MTX concentrations
Flobaum and Meyers,20 with 5 of 9 patients and 1 of 11 decreased from a median of 89 ␮mol/L and 6.4
patients, respectively, reported to have renal toxicity ␮mol/L to a median of 1 ␮mol/L and ⬍ 0.05 ␮mol/L
ⱖ Grade 3. The median time to recovery of renal within 15 minutes of CPDG2 administration for pa-
function for the 40 patients, as defined by the individ- tients with osteosarcoma and non-Hodgkin lym-
ual studies, was 16 days (range, 4 – 48 days). phoma (NHL) or ALL, respectively. A rebound increase
in plasma MTX concentrations was observed in 60% of
MTX Pharmacokinetics and Recovery of Renal Function patients who were treated with CPDG2, which reached
after CPDG2 Administration 2.8%, 8.8%, and 2.5% of the MTX concentration prior
In patients with HDMTX-induced renal dysfunction, to administration of CPDG2 for patients with osteosar-
CPDG2 was tolerated well. Four of 20 patients de- coma (n ⫽ 7 patients), NHL or ALL (n ⫽ 5 patients),
scribed mild symptoms associated with CPDG2 ad- and gastric carcinoma (n ⫽ 1 patient), respectively.
ministration, including a feeling of warmth, tingling For 17 patients with complete data regarding renal
fingers, head pressure, flushing, shaking, and burning recovery, serum creatinine levels peaked at a median
of face and extremities. CPDG2 administration re- of 3.4 mg/dL (range, from 0.8 mg/dL in an infant age
sulted in a rapid 95.6 –99.6% reduction (median, 3 months to 12.5 mg/dL) and returned to values within
 HDMTX Nephrotoxicity in Osteosarcoma/Widemann et al. 2227

TABLE 3
Recovery of Renal Function after Methotrexate-Induced Renal Dysfunctiona

No. of Peak serum Cr Time to renal renal

Study Year patientsb levels (mg/dL) Treatmentc recovery (days) Definition of recovery

Hande et al.21 1977 1 3.4 Dialysis 20 Recovery of function

Abelson et al.10 1983 8 8.95, 2.2, 1.1, 4.1, Thymidine 21, 10, 9, 15, 17, 11, 7, 8 Serum Cr 1.5 ⫻ baseline
5.2, 1.35, 2.1, 0.9
Molina et al.101 1987 1 4.0 Charcoal hemoperfusion 20 Serum Cr WNL
Relling et al.24 1988 1 5.0 Hemodialysis ⫹ hemoperfusion 24 Serum Cr WNL
Stark et al.11 1989 2 3.9 Supportive 19, 12 Serum Cr WNL
Thierry et al.102 1989 1 4.0 Hemodialysis/plasma exchange 15 Hemodialysis stopped
Grimes et al.25 1990 1 5.0 Charcoal hemoperfusion 17 Serum Cr WNL
McIvor98 1991 1 4.5 Charcoal hemoperfusion 28 Serum Cr WNL
Kawabata et al.26 1995 1 ⬇ 3.7 Plasma perfusion ⫹ hemodialysis 29 Hemodialysis stopped
Benezet et al.99 1997 1 7.6 Exchange transfusion 23 Serum Cr WNL
Flobaum and Meyers20 1999 11 1.7, 3.0, 1.8, 2.6, 1.9, Hemoperfusion (2 patients) 16, 10, 6, 10, 8, 4, 5, 25, 3, Serum Cr 1.5 ⫻ baseline
2.0, 1.7, 2.5, 2.0, 14, 21
2.7, 7.8
van den Bongard et al.103 2000 1 4.8 Thymidine 17 Serum Cr ⬇ 1.7 ⫻
baseline
Shinozaki et al.100 2000 1 ⬇ 3.7 Plasma exchange, cholestyramine 20 Serum Cr ⬇ 1.5 ⫻
baseline
Bielack (trial survey) 1980–2000 9 WHO G2 and G3 (4 Plasmapheresis (1 patient) 38, 16, 40, 8, 34, 21, 14, 48, Serum Cr 1.0 ⫻ baseline
patients each), 16 (0.9–2.0)d
G4 (1 patient)

Cr: creatinine; WNL: within normal limits; WHO: World Health Organization; G2–G4: Grade 2–4.
a
Treatment of patients did not include carboxypeptidase-G2. Published literature was reviewed from 1977 to 2002 on recovery of renal function in patients with methotrexate-induced renal dysfunction.
b
Patients were included only if days to recovery data were available.
c
Treatment included leucovorin for all patients.
d
Numbers indicate median, with ranges shown in parentheses

normal limits (median, 1.1 mg/dL; range, 0.3–1.3 mg/ the incidence of MTX-induced renal dysfunction
dL), corresponding to a median of 1.4 times the base- among all patients receiving HDMTX may be higher.
line creatinine level at a median of 22 days (range, Although the incidence and mortality of HDMTX-in-
5– 40 days) after the initiation of the MTX infusion. duced renal dysfunction appear to have decreased
Additional MTX infusions were administered to 5 pa- significantly since the 1970s,13 nephrotoxicity contin-
tients after recovery of renal function (full dose, n ⫽ 1 ues to occur and may be fatal.
patient; 20 –75% of the protocol-prescribed dose, n The cornerstone of successful treatment for pa-
⫽ 4 patients) without recurrence of nephrotoxicity. tients with HDMTX-induced renal dysfunction in-
cludes early recognition of this toxicity and prompt
DISCUSSION institution of increased doses of LV.9,20 However, pa-
Based on our literature review and information avail- tients are at greater risk for the development of life-
able from our databases (see Table 1), approximately threatening MTX toxicities if MTX renal excretion is
1.8% of patients with osteosarcoma who are treated delayed and plasma MTX concentrations remain ele-
with HDMTX develop significant nephrotoxicity at vated, even though they are receiving high doses of LV.
some time during treatment, and the mortality among The large number of publications describing invasive
these patients is estimated at 4.4%. Limitations of this methods that attempt to address the underlying prob-
estimate include the following: nephrotoxicity was not lem of impaired MTX elimination (Table 2) reflects the
defined uniformly across studies, trials were not de- necessity to provide an alternative route of MTX elim-
signed to capture data concerning nephrotoxicity ination in patients with renal dysfunction. This review
comprehensively, and few published studies included suggests that these mechanical methods have variable
a comprehensive description of MTX-related toxici- and limited effectiveness in removing MTX. Rebound
ties. In addition, only patients entered on clinical tri- increases in MTX concentrations to levels approach-
als, who may be more likely to receive optimal sup- ing those that existed prior to institution of the dialy-
portive care, were included in the estimate. Therefore, sis-based method have been reported. The most effec-
2228 CANCER May 15, 2004 / Volume 100 / Number 10
tive dialysis-based methods for MTX removal
currently in use are charcoal hemoperfusion in com-
bination with hemodialysis or high-flux hemodialy-
sis.24,25,28,70 Such methods of mechanical MTX re-
moval, however, may not be available readily outside
of major medical centers and include the risks asso-
ciated with the insertion of vascular-access devices,
the transfusion of blood products, electrolyte imbal-
ances, and the risk of bleeding secondary to hepa-
rinization, thrombocytopenia, and anemia.24,25,70,74
Compared with dialysis-based methods, the use of
CPDG2 is tolerated well and results in a more pro-
found, rapid, and consistent decrease in plasma MTX
concentrations, and rebounds ⬍ 10% in plasma MTX
concentrations were observed in only 60% of patients
who were treated with CPDG2.34,35
A retrospective comparison of the recovery of re-
nal function after supportive therapy that included
dialysis versus CPDG2 in patients with HDMTX-in-
duced renal dysfunction is limited by the varying de-
grees of renal damage and the differing of definitions
used in the literature to define renal recovery. In the
majority of patients included in our literature review,
recovery of renal function was defined not as a return
of serum creatinine to pretreatment (baseline) levels
but as a return to a serum creatinine levels within 1.5
⫻ baseline levels or as the ability to discontinue dial-
ysis-based methods. With this definition, the median
time to recovery of renal function in patients with
HDMTX-induced renal dysfunction who were treated
with supportive measures, including dialysis-based
methods but not CPDG2, was 16 days.
A theoretic concern regarding the use of CPDG2
is that the rapid formation of the MTX metabolite,
DAMPA, which is approximately 10-fold less soluble
than MTX, could lead to further renal toxicity by
precipitation in the renal tubules.75 In 17 patients
who received CPDG2 for MTX-induced renal dys-
function, serum creatinine declined to levels below
the upper limit of normal, corresponding to a me-
dian serum creatinine level 1.4 times the pre-HD-
MTX level at a median of 22 days after the admin-
istration of CPDG2.34,35 The severity of renal injury
in these CPDG2-treated patients, as measured by the
peak serum creatinine level (median, 3.4 mg/dL),
was worse compared with the severity in patients
who were treated with supportive measures without
CPDG2 or dialysis (median peak creatinine level, 2.1
mg/dL) but less compared with the severity in pa-
tients who underwent dialysis-based methods but
did not receive CPDG2 (median peak creatinine
level, 3.9 mg/dL). For patients with osteosarcoma
who received CPDG2 (n ⫽ 11 patients)34,35 for MTX-
induced nephrotoxicity and delayed MTX clearance,
the median plasma MTX concentration 44 hours
after the initiation of the HDMTX infusion was 485
␮M, compared with 16.3 ␮M at 48 hours for patients
with osteosarcoma (n ⫽ 13 patients) who received
LV as the only rescue agent, according to a report by
Flobaum and Meyers.20 The median peak serum
creatinine level was 5.0 mg/dL (range, 2.2–12.5 mg/
dL) for the CPDG2-treated patients and 2.0 mg/dL
(1.7–7.8 mg/dL) for patients who received only LV.
This indicates that patients with osteosarcoma who
received CPDG2 had experienced a greater degree of
renal injury prior to CPDG2 administration com-
pared with the patients with osteosarcoma reported
by Flobaum and Meyers, which may account for the
prolonged time to renal recovery in patients who
were treated with CPDG2.
The degree of renal injury (Grade 3– 4 toxicity in 5
of 9 patients) and the time to recovery of renal func-
tion (median, 21 days) for patients who were entered
on COSS trials and who did not receive CPDG2 ap-
pears more comparable to those of the patients who
received CPDG2. These data suggest that the admin-
istration of CPDG2 does not result in prolonged renal
recovery compared with patients who had similar de-
grees of renal toxicity and were treated with support-
ive or dialysis-based methods. The potential benefits
of the administration of CPDG2 over the use of dialy-
sis-based methods to lower plasma MTX concentra-
tions in the treatment of HDMTX-induced renal dys-
function include the more rapid and profound
lowering of plasma MTX concentrations, the ease of
use (single intravenous infusion), the potential ready
availability at the treating institutions, and the lack of
a need for the insertion of a new vascular-access de-
vice and its associated risks.
HDMTX-induced renal dysfunction continues to
occur with an approximate frequency of 1.8% in pa-
tients with osteosarcoma who are treated on clinical
protocols. Dialysis-based methods of MTX removal
are used frequently but have variable and limited ef-
fectiveness compared with the rapid and marked de-
crease in plasma MTX concentrations after the admin-
istration of CPDG2. CPDG2 is tolerated well and does
not appear to delay renal recovery compared with
patients who have comparable renal toxicity and are
treated with supportive treatment or dialysis-based
methods. Therefore, the use of CPDG2 instead of di-
alysis-based methods is recommended to reduce
plasma MTX concentrations in patients with HDMTX-
induced renal dysfunction.
 HDMTX Nephrotoxicity in Osteosarcoma/Widemann et al.
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